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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Common breast cancer susceptibility alleles are associated with tumour subtypes in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers: results from the Consortium of Investigators of Modifiers of <italic>BRCA1/2</italic>
</title>
<author><name sortKey="Mulligan, Anna Marie" sort="Mulligan, Anna Marie" uniqKey="Mulligan A" first="Anna Marie" last="Mulligan">Anna Marie Mulligan</name>
<affiliation><nlm:aff id="I1">Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J" last="Couch">Fergus J. Couch</name>
<affiliation><nlm:aff id="I2">Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barrowdale, Daniel" sort="Barrowdale, Daniel" uniqKey="Barrowdale D" first="Daniel" last="Barrowdale">Daniel Barrowdale</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Domchek, Susan M" sort="Domchek, Susan M" uniqKey="Domchek S" first="Susan M" last="Domchek">Susan M. Domchek</name>
<affiliation><nlm:aff id="I4">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eccles, Diana" sort="Eccles, Diana" uniqKey="Eccles D" first="Diana" last="Eccles">Diana Eccles</name>
<affiliation><nlm:aff id="I5">Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nevanlinna, Heli" sort="Nevanlinna, Heli" uniqKey="Nevanlinna H" first="Heli" last="Nevanlinna">Heli Nevanlinna</name>
<affiliation><nlm:aff id="I6">Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ramus, Susan J" sort="Ramus, Susan J" uniqKey="Ramus S" first="Susan J" last="Ramus">Susan J. Ramus</name>
<affiliation><nlm:aff id="I7">Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N Soto Street, Los Angeles, CA 90089-9237, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Robson, Mark" sort="Robson, Mark" uniqKey="Robson M" first="Mark" last="Robson">Mark Robson</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sherman, Mark" sort="Sherman, Mark" uniqKey="Sherman M" first="Mark" last="Sherman">Mark Sherman</name>
<affiliation><nlm:aff id="I9">National Cancer Institute, Division of Cancer Epidemiology and Genetics, Hormonal and Reproductive Epidemiology Branch, 6120 Executive Blvd., Rockville, MD 20852, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name>
<affiliation><nlm:aff id="I10">Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name>
<affiliation><nlm:aff id="I11">Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Andrew" sort="Lee, Andrew" uniqKey="Lee A" first="Andrew" last="Lee">Andrew Lee</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name>
<affiliation><nlm:aff id="I10">Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M" last="Sinilnikova">Olga M. Sinilnikova</name>
<affiliation><nlm:aff id="I12">Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="I13">INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Janavicius, Ramunas" sort="Janavicius, Ramunas" uniqKey="Janavicius R" first="Ramunas" last="Janavicius">Ramunas Janavicius</name>
<affiliation><nlm:aff id="I14">Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, Santariskiu st 2, LT-08661 Vilnius and State Research Institute Innovative Medicine Center, Zygimantu st. 9, LT-01102 Vilnius, Lithuania</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hansen, Thomas Vo" sort="Hansen, Thomas Vo" uniqKey="Hansen T" first="Thomas Vo" last="Hansen">Thomas Vo Hansen</name>
<affiliation><nlm:aff id="I15">Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nielsen, Finn C" sort="Nielsen, Finn C" uniqKey="Nielsen F" first="Finn C" last="Nielsen">Finn C. Nielsen</name>
<affiliation><nlm:aff id="I15">Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ejlertsen, Bent" sort="Ejlertsen, Bent" uniqKey="Ejlertsen B" first="Bent" last="Ejlertsen">Bent Ejlertsen</name>
<affiliation><nlm:aff id="I16">Department of Oncology, Rigshospitalet Bldg. 4262, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Osorio, Ana" sort="Osorio, Ana" uniqKey="Osorio A" first="Ana" last="Osorio">Ana Osorio</name>
<affiliation><nlm:aff id="I17">Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mu Oz Repeto, Ivan" sort="Mu Oz Repeto, Ivan" uniqKey="Mu Oz Repeto I" first="Iván" last="Mu Oz-Repeto">Iván Mu Oz-Repeto</name>
<affiliation><nlm:aff id="I17">Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Duran, Mercedes" sort="Duran, Mercedes" uniqKey="Duran M" first="Mercedes" last="Durán">Mercedes Durán</name>
<affiliation><nlm:aff id="I18">Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), C/Sanz y Forés, N° 3, Valladolid, 47003, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Godino, Javier" sort="Godino, Javier" uniqKey="Godino J" first="Javier" last="Godino">Javier Godino</name>
<affiliation><nlm:aff id="I19">Instituto de investigación sanitaria de Aragón (IIS), Hospital clinico Universitario "Lozano Blesa", San Juan Bosco 15, Zaragoza, 50009, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pertesi, Maroulio" sort="Pertesi, Maroulio" uniqKey="Pertesi M" first="Maroulio" last="Pertesi">Maroulio Pertesi</name>
<affiliation><nlm:aff id="I20">Molecular Diagnostics Laboratory, IRRP, National Center for Scientific Research Demokritos, Patriarchou Gregoriou E' & Neapoleos Str, Ag. Paraskevi 15310, Athens, Greece</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benítez">Javier Benítez</name>
<affiliation><nlm:aff id="I21">Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Peterlongo, Paolo" sort="Peterlongo, Paolo" uniqKey="Peterlongo P" first="Paolo" last="Peterlongo">Paolo Peterlongo</name>
<affiliation><nlm:aff id="I22">Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, 20133 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, 20139 Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Manoukian, Siranoush" sort="Manoukian, Siranoush" uniqKey="Manoukian S" first="Siranoush" last="Manoukian">Siranoush Manoukian</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Peissel, Bernard" sort="Peissel, Bernard" uniqKey="Peissel B" first="Bernard" last="Peissel">Bernard Peissel</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zaffaroni, Daniela" sort="Zaffaroni, Daniela" uniqKey="Zaffaroni D" first="Daniela" last="Zaffaroni">Daniela Zaffaroni</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cattaneo, Elisa" sort="Cattaneo, Elisa" uniqKey="Cattaneo E" first="Elisa" last="Cattaneo">Elisa Cattaneo</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bonanni, Bernardo" sort="Bonanni, Bernardo" uniqKey="Bonanni B" first="Bernardo" last="Bonanni">Bernardo Bonanni</name>
<affiliation><nlm:aff id="I24">Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, via Ripamonti 435, Milan, 20141, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Viel, Alessandra" sort="Viel, Alessandra" uniqKey="Viel A" first="Alessandra" last="Viel">Alessandra Viel</name>
<affiliation><nlm:aff id="I25">Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pasini, Barbara" sort="Pasini, Barbara" uniqKey="Pasini B" first="Barbara" last="Pasini">Barbara Pasini</name>
<affiliation><nlm:aff id="I26">Department of Genetics, Biology and BiochemIstry, University of Turin, Turin, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Papi, Laura" sort="Papi, Laura" uniqKey="Papi L" first="Laura" last="Papi">Laura Papi</name>
<affiliation><nlm:aff id="I27">Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Firenze, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ottini, Laura" sort="Ottini, Laura" uniqKey="Ottini L" first="Laura" last="Ottini">Laura Ottini</name>
<affiliation><nlm:aff id="I28">Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Savarese, Antonella" sort="Savarese, Antonella" uniqKey="Savarese A" first="Antonella" last="Savarese">Antonella Savarese</name>
<affiliation><nlm:aff id="I29">Division of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bernard, Loris" sort="Bernard, Loris" uniqKey="Bernard L" first="Loris" last="Bernard">Loris Bernard</name>
<affiliation><nlm:aff id="I30">Department of Experimental Oncology, Istituto Europeo di Oncologia. Milan, Italy; Consortium for Genomics Technology (Cogentech), Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name>
<affiliation><nlm:aff id="I22">Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, 20133 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, 20139 Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name>
<affiliation><nlm:aff id="I31">Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Verheus, Martijn" sort="Verheus, Martijn" uniqKey="Verheus M" first="Martijn" last="Verheus">Martijn Verheus</name>
<affiliation><nlm:aff id="I32">Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meijers Heijboer, Hanne Ej" sort="Meijers Heijboer, Hanne Ej" uniqKey="Meijers Heijboer H" first="Hanne Ej" last="Meijers-Heijboer">Hanne Ej Meijers-Heijboer</name>
<affiliation><nlm:aff id="I33">Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wijnen, Juul" sort="Wijnen, Juul" uniqKey="Wijnen J" first="Juul" last="Wijnen">Juul Wijnen</name>
<affiliation><nlm:aff id="I34">Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="G Mez Garcia, Encarna B" sort="G Mez Garcia, Encarna B" uniqKey="G Mez Garcia E" first="Encarna B" last="G Mez García">Encarna B. G Mez García</name>
<affiliation><nlm:aff id="I35">Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nelen, Marcel R" sort="Nelen, Marcel R" uniqKey="Nelen M" first="Marcel R" last="Nelen">Marcel R. Nelen</name>
<affiliation><nlm:aff id="I36">Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kets, C Marleen" sort="Kets, C Marleen" uniqKey="Kets C" first="C Marleen" last="Kets">C Marleen Kets</name>
<affiliation><nlm:aff id="I37">Department of Human Genetics 836, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seynaeve, Caroline" sort="Seynaeve, Caroline" uniqKey="Seynaeve C" first="Caroline" last="Seynaeve">Caroline Seynaeve</name>
<affiliation><nlm:aff id="I38">Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tilanus Linthorst, Madeleine Ma" sort="Tilanus Linthorst, Madeleine Ma" uniqKey="Tilanus Linthorst M" first="Madeleine Ma" last="Tilanus-Linthorst">Madeleine Ma Tilanus-Linthorst</name>
<affiliation><nlm:aff id="I39">Department of Surgical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Der Luijt, Rob B" sort="Van Der Luijt, Rob B" uniqKey="Van Der Luijt R" first="Rob B" last="Van Der Luijt">Rob B. Van Der Luijt</name>
<affiliation><nlm:aff id="I40">Department of Medical Genetics, University Medical Center Utrecht, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Os, Theo Van" sort="Os, Theo Van" uniqKey="Os T" first="Theo Van" last="Os">Theo Van Os</name>
<affiliation><nlm:aff id="I41">Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rookus, Matti" sort="Rookus, Matti" uniqKey="Rookus M" first="Matti" last="Rookus">Matti Rookus</name>
<affiliation><nlm:aff id="I32">Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frost, Debra" sort="Frost, Debra" uniqKey="Frost D" first="Debra" last="Frost">Debra Frost</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jones, J Louise" sort="Jones, J Louise" uniqKey="Jones J" first="J Louise" last="Jones">J Louise Jones</name>
<affiliation><nlm:aff id="I42">Barts Cancer Institute, Queen Mary University of London, Centre for Tumour Biology, Charterhouse Square, London, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Evans, D Gareth" sort="Evans, D Gareth" uniqKey="Evans D" first="D Gareth" last="Evans">D Gareth Evans</name>
<affiliation><nlm:aff id="I43">Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lalloo, Fiona" sort="Lalloo, Fiona" uniqKey="Lalloo F" first="Fiona" last="Lalloo">Fiona Lalloo</name>
<affiliation><nlm:aff id="I43">Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eeles, Ros" sort="Eeles, Ros" uniqKey="Eeles R" first="Ros" last="Eeles">Ros Eeles</name>
<affiliation><nlm:aff id="I44">Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Izatt, Louise" sort="Izatt, Louise" uniqKey="Izatt L" first="Louise" last="Izatt">Louise Izatt</name>
<affiliation><nlm:aff id="I45">Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Adlard, Julian" sort="Adlard, Julian" uniqKey="Adlard J" first="Julian" last="Adlard">Julian Adlard</name>
<affiliation><nlm:aff id="I46">Yorkshire Regional Genetics Service, Leeds, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Davidson, Rosemarie" sort="Davidson, Rosemarie" uniqKey="Davidson R" first="Rosemarie" last="Davidson">Rosemarie Davidson</name>
<affiliation><nlm:aff id="I47">Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cook, Jackie" sort="Cook, Jackie" uniqKey="Cook J" first="Jackie" last="Cook">Jackie Cook</name>
<affiliation><nlm:aff id="I48">Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Donaldson, Alan" sort="Donaldson, Alan" uniqKey="Donaldson A" first="Alan" last="Donaldson">Alan Donaldson</name>
<affiliation><nlm:aff id="I49">Clinical Genetics Department, St Michael's Hospital, Bristol, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dorkins, Huw" sort="Dorkins, Huw" uniqKey="Dorkins H" first="Huw" last="Dorkins">Huw Dorkins</name>
<affiliation><nlm:aff id="I50">North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gregory, Helen" sort="Gregory, Helen" uniqKey="Gregory H" first="Helen" last="Gregory">Helen Gregory</name>
<affiliation><nlm:aff id="I51">North of Scotland Regional Genetics Service, NHS Grampian and University of Aberdeen, Foresterhill, Aberdeen, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eason, Jacqueline" sort="Eason, Jacqueline" uniqKey="Eason J" first="Jacqueline" last="Eason">Jacqueline Eason</name>
<affiliation><nlm:aff id="I52">Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Houghton, Catherine" sort="Houghton, Catherine" uniqKey="Houghton C" first="Catherine" last="Houghton">Catherine Houghton</name>
<affiliation><nlm:aff id="I53">Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barwell, Julian" sort="Barwell, Julian" uniqKey="Barwell J" first="Julian" last="Barwell">Julian Barwell</name>
<affiliation><nlm:aff id="I54">Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Side, Lucy E" sort="Side, Lucy E" uniqKey="Side L" first="Lucy E" last="Side">Lucy E. Side</name>
<affiliation><nlm:aff id="I55">North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mccann, Emma" sort="Mccann, Emma" uniqKey="Mccann E" first="Emma" last="Mccann">Emma Mccann</name>
<affiliation><nlm:aff id="I56">All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Murray, Alex" sort="Murray, Alex" uniqKey="Murray A" first="Alex" last="Murray">Alex Murray</name>
<affiliation><nlm:aff id="I57">All Wales Medical Genetics Services, Singleton Hospital, Swansea, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Peock, Susan" sort="Peock, Susan" uniqKey="Peock S" first="Susan" last="Peock">Susan Peock</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Godwin, Andrew K" sort="Godwin, Andrew K" uniqKey="Godwin A" first="Andrew K" last="Godwin">Andrew K. Godwin</name>
<affiliation><nlm:aff id="I58">Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K" last="Schmutzler">Rita K. Schmutzler</name>
<affiliation><nlm:aff id="I11">Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rhiem, Kerstin" sort="Rhiem, Kerstin" uniqKey="Rhiem K" first="Kerstin" last="Rhiem">Kerstin Rhiem</name>
<affiliation><nlm:aff id="I11">Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Engel, Christoph" sort="Engel, Christoph" uniqKey="Engel C" first="Christoph" last="Engel">Christoph Engel</name>
<affiliation><nlm:aff id="I59">Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name>
<affiliation><nlm:aff id="I60">Department of Gynaecology and Obstetrics, Division of Tumour Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ruehl, Ina" sort="Ruehl, Ina" uniqKey="Ruehl I" first="Ina" last="Ruehl">Ina Ruehl</name>
<affiliation><nlm:aff id="I61">Department of Gynaecology and Obstetrics, Ludwig-Maximillians University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Arnold, Norbert" sort="Arnold, Norbert" uniqKey="Arnold N" first="Norbert" last="Arnold">Norbert Arnold</name>
<affiliation><nlm:aff id="I62">Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Christian-Albrechts University, Kiel, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Niederacher, Dieter" sort="Niederacher, Dieter" uniqKey="Niederacher D" first="Dieter" last="Niederacher">Dieter Niederacher</name>
<affiliation><nlm:aff id="I63">Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sutter, Christian" sort="Sutter, Christian" uniqKey="Sutter C" first="Christian" last="Sutter">Christian Sutter</name>
<affiliation><nlm:aff id="I64">Institute of Human Genetics, Department of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Deissler, Helmut" sort="Deissler, Helmut" uniqKey="Deissler H" first="Helmut" last="Deissler">Helmut Deissler</name>
<affiliation><nlm:aff id="I65">Department of Gynaecology and Obstetrics, University Hospital, Ulm, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gadzicki, Dorothea" sort="Gadzicki, Dorothea" uniqKey="Gadzicki D" first="Dorothea" last="Gadzicki">Dorothea Gadzicki</name>
<affiliation><nlm:aff id="I66">Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kast, Karin" sort="Kast, Karin" uniqKey="Kast K" first="Karin" last="Kast">Karin Kast</name>
<affiliation><nlm:aff id="I67">Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University, Dresden, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Preisler Adams, Sabine" sort="Preisler Adams, Sabine" uniqKey="Preisler Adams S" first="Sabine" last="Preisler-Adams">Sabine Preisler-Adams</name>
<affiliation><nlm:aff id="I68">Institute of Human Genetics, University of Münster, Münster, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Varon Mateeva, Raymonda" sort="Varon Mateeva, Raymonda" uniqKey="Varon Mateeva R" first="Raymonda" last="Varon-Mateeva">Raymonda Varon-Mateeva</name>
<affiliation><nlm:aff id="I69">Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schoenbuchner, Ines" sort="Schoenbuchner, Ines" uniqKey="Schoenbuchner I" first="Ines" last="Schoenbuchner">Ines Schoenbuchner</name>
<affiliation><nlm:aff id="I70">Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fiebig, Britta" sort="Fiebig, Britta" uniqKey="Fiebig B" first="Britta" last="Fiebig">Britta Fiebig</name>
<affiliation><nlm:aff id="I71">Institute of Human Genetics, University Regensburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Heinritz, Wolfram" sort="Heinritz, Wolfram" uniqKey="Heinritz W" first="Wolfram" last="Heinritz">Wolfram Heinritz</name>
<affiliation><nlm:aff id="I72">Institute of Human Genetics, University Leipzig, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sch Fer, Dieter" sort="Sch Fer, Dieter" uniqKey="Sch Fer D" first="Dieter" last="Sch Fer">Dieter Sch Fer</name>
<affiliation><nlm:aff id="I73">Institute of Human Genetics, University Hospital, Frankfurt a.M., Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gevensleben, Heidrun" sort="Gevensleben, Heidrun" uniqKey="Gevensleben H" first="Heidrun" last="Gevensleben">Heidrun Gevensleben</name>
<affiliation><nlm:aff id="I74">Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Caux Moncoutier, Virginie" sort="Caux Moncoutier, Virginie" uniqKey="Caux Moncoutier V" first="Virginie" last="Caux-Moncoutier">Virginie Caux-Moncoutier</name>
<affiliation><nlm:aff id="I75">Service de Génétique Oncologique, Institut Curie, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fassy Colcombet, Marion" sort="Fassy Colcombet, Marion" uniqKey="Fassy Colcombet M" first="Marion" last="Fassy-Colcombet">Marion Fassy-Colcombet</name>
<affiliation><nlm:aff id="I75">Service de Génétique Oncologique, Institut Curie, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cornelis, Francois" sort="Cornelis, Francois" uniqKey="Cornelis F" first="François" last="Cornelis">François Cornelis</name>
<affiliation><nlm:aff id="I76">Genetic Unit, Avicenne Hospital, Assitance Publique-Hôpitaux de Paris, Paris, France; Sud-Francilien Hospital, Evry-Corbeil, France; University Hospital, Clermont-Ferrand, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mazoyer, Sylvie" sort="Mazoyer, Sylvie" uniqKey="Mazoyer S" first="Sylvie" last="Mazoyer">Sylvie Mazoyer</name>
<affiliation><nlm:aff id="I13">INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Leone, Melanie" sort="Leone, Melanie" uniqKey="Leone M" first="Mélanie" last="Léoné">Mélanie Léoné</name>
<affiliation><nlm:aff id="I12">Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Boutry Kryza, Nadia" sort="Boutry Kryza, Nadia" uniqKey="Boutry Kryza N" first="Nadia" last="Boutry-Kryza">Nadia Boutry-Kryza</name>
<affiliation><nlm:aff id="I12">Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hardouin, Agnes" sort="Hardouin, Agnes" uniqKey="Hardouin A" first="Agnès" last="Hardouin">Agnès Hardouin</name>
<affiliation><nlm:aff id="I77">Centre François Baclesse, Caen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Berthet, Pascaline" sort="Berthet, Pascaline" uniqKey="Berthet P" first="Pascaline" last="Berthet">Pascaline Berthet</name>
<affiliation><nlm:aff id="I77">Centre François Baclesse, Caen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Muller, Daniele" sort="Muller, Daniele" uniqKey="Muller D" first="Danièle" last="Muller">Danièle Muller</name>
<affiliation><nlm:aff id="I78">Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fricker, Jean Pierre" sort="Fricker, Jean Pierre" uniqKey="Fricker J" first="Jean-Pierre" last="Fricker">Jean-Pierre Fricker</name>
<affiliation><nlm:aff id="I78">Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mortemousque, Isabelle" sort="Mortemousque, Isabelle" uniqKey="Mortemousque I" first="Isabelle" last="Mortemousque">Isabelle Mortemousque</name>
<affiliation><nlm:aff id="I79">Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pujol, Pascal" sort="Pujol, Pascal" uniqKey="Pujol P" first="Pascal" last="Pujol">Pascal Pujol</name>
<affiliation><nlm:aff id="I80">Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Coupier, Isabelle" sort="Coupier, Isabelle" uniqKey="Coupier I" first="Isabelle" last="Coupier">Isabelle Coupier</name>
<affiliation><nlm:aff id="I80">Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lebrun, Marine" sort="Lebrun, Marine" uniqKey="Lebrun M" first="Marine" last="Lebrun">Marine Lebrun</name>
<affiliation><nlm:aff id="I81">Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kientz, Caroline" sort="Kientz, Caroline" uniqKey="Kientz C" first="Caroline" last="Kientz">Caroline Kientz</name>
<affiliation><nlm:aff id="I81">Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Longy, Michel" sort="Longy, Michel" uniqKey="Longy M" first="Michel" last="Longy">Michel Longy</name>
<affiliation><nlm:aff id="I82">Cancer Genetics Unit, INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sevenet, Nicolas" sort="Sevenet, Nicolas" uniqKey="Sevenet N" first="Nicolas" last="Sevenet">Nicolas Sevenet</name>
<affiliation><nlm:aff id="I82">Cancer Genetics Unit, INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stoppa Lyonnet, Dominique" sort="Stoppa Lyonnet, Dominique" uniqKey="Stoppa Lyonnet D" first="Dominique" last="Stoppa-Lyonnet">Dominique Stoppa-Lyonnet</name>
<affiliation><nlm:aff id="I75">Service de Génétique Oncologique, Institut Curie, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="I83">Unité INSERM U830, Institut Curie, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Isaacs, Claudine" sort="Isaacs, Claudine" uniqKey="Isaacs C" first="Claudine" last="Isaacs">Claudine Isaacs</name>
<affiliation><nlm:aff id="I84">Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Caldes, Trinidad" sort="Caldes, Trinidad" uniqKey="Caldes T" first="Trinidad" last="Caldes">Trinidad Caldes</name>
<affiliation><nlm:aff id="I85">Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="De La Hoya, Miguel" sort="De La Hoya, Miguel" uniqKey="De La Hoya M" first="Miguel" last="De La Hoya">Miguel De La Hoya</name>
<affiliation><nlm:aff id="I85">Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Heikkinen, Tuomas" sort="Heikkinen, Tuomas" uniqKey="Heikkinen T" first="Tuomas" last="Heikkinen">Tuomas Heikkinen</name>
<affiliation><nlm:aff id="I6">Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Aittom Ki, Kristiina" sort="Aittom Ki, Kristiina" uniqKey="Aittom Ki K" first="Kristiina" last="Aittom Ki">Kristiina Aittom Ki</name>
<affiliation><nlm:aff id="I86">Department of Clinical Genetics, Helsinki University Central Hospital, Meilahdentie 2, 00290 Helsinki, Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Blanco, Ignacio" sort="Blanco, Ignacio" uniqKey="Blanco I" first="Ignacio" last="Blanco">Ignacio Blanco</name>
<affiliation><nlm:aff id="I87">Hereditary Cancer Program, Institut Català d'Oncologia, Hospital Duran i Reynals - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lazaro, Conxi" sort="Lazaro, Conxi" uniqKey="Lazaro C" first="Conxi" last="Lazaro">Conxi Lazaro</name>
<affiliation><nlm:aff id="I87">Hereditary Cancer Program, Institut Català d'Oncologia, Hospital Duran i Reynals - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barkardottir, Rosa B" sort="Barkardottir, Rosa B" uniqKey="Barkardottir R" first="Rosa B" last="Barkardottir">Rosa B. Barkardottir</name>
<affiliation><nlm:aff id="I88">Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland, Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Soucy, Penny" sort="Soucy, Penny" uniqKey="Soucy P" first="Penny" last="Soucy">Penny Soucy</name>
<affiliation><nlm:aff id="I89">Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dumont, Martine" sort="Dumont, Martine" uniqKey="Dumont M" first="Martine" last="Dumont">Martine Dumont</name>
<affiliation><nlm:aff id="I89">Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name>
<affiliation><nlm:aff id="I90">Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada; Canada Research Chair in Oncogenetics, Department of Molecular Medicine, Faculty of Medicine, Laval University, QC, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Montagna, Marco" sort="Montagna, Marco" uniqKey="Montagna M" first="Marco" last="Montagna">Marco Montagna</name>
<affiliation><nlm:aff id="I91">Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tognazzo, Silvia" sort="Tognazzo, Silvia" uniqKey="Tognazzo S" first="Silvia" last="Tognazzo">Silvia Tognazzo</name>
<affiliation><nlm:aff id="I91">Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="D Andrea, Emma" sort="D Andrea, Emma" uniqKey="D Andrea E" first="Emma" last="D'Andrea">Emma D'Andrea</name>
<affiliation><nlm:aff id="I92">Department of Oncology and Surgical Sciences, University of Padua and Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fox, Stephen" sort="Fox, Stephen" uniqKey="Fox S" first="Stephen" last="Fox">Stephen Fox</name>
<affiliation><nlm:aff id="I93">Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yan, Max" sort="Yan, Max" uniqKey="Yan M" first="Max" last="Yan">Max Yan</name>
<affiliation><nlm:aff id="I94">Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rebbeck, Tim" sort="Rebbeck, Tim" uniqKey="Rebbeck T" first="Tim" last="Rebbeck">Tim Rebbeck</name>
<affiliation><nlm:aff id="I95">Abramson Cancer Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olopade, Olufunmilayo I" sort="Olopade, Olufunmilayo I" uniqKey="Olopade O" first="Olufunmilayo I" last="Olopade">Olufunmilayo I. Olopade</name>
<affiliation><nlm:aff id="I96">University of Chicago, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Weitzel, Jeffrey N" sort="Weitzel, Jeffrey N" uniqKey="Weitzel J" first="Jeffrey N" last="Weitzel">Jeffrey N. Weitzel</name>
<affiliation><nlm:aff id="I97">City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lynch, Henry T" sort="Lynch, Henry T" uniqKey="Lynch H" first="Henry T" last="Lynch">Henry T. Lynch</name>
<affiliation><nlm:aff id="I98">Departments of Medicine, and Preventive Medicine and Public Health, Creighton University, Omaha, NE, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ganz, Patricia A" sort="Ganz, Patricia A" uniqKey="Ganz P" first="Patricia A" last="Ganz">Patricia A. Ganz</name>
<affiliation><nlm:aff id="I99">Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tomlinson, Gail E" sort="Tomlinson, Gail E" uniqKey="Tomlinson G" first="Gail E" last="Tomlinson">Gail E. Tomlinson</name>
<affiliation><nlm:aff id="I100">Department of Internal Medicine and Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX; USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wang, Xianshu" sort="Wang, Xianshu" uniqKey="Wang X" first="Xianshu" last="Wang">Xianshu Wang</name>
<affiliation><nlm:aff id="I2">Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fredericksen, Zachary" sort="Fredericksen, Zachary" uniqKey="Fredericksen Z" first="Zachary" last="Fredericksen">Zachary Fredericksen</name>
<affiliation><nlm:aff id="I101">Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pankratz, Vernon S" sort="Pankratz, Vernon S" uniqKey="Pankratz V" first="Vernon S" last="Pankratz">Vernon S. Pankratz</name>
<affiliation><nlm:aff id="I101">Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lindor, Noralane M" sort="Lindor, Noralane M" uniqKey="Lindor N" first="Noralane M" last="Lindor">Noralane M. Lindor</name>
<affiliation><nlm:aff id="I102">Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Szabo, Csilla" sort="Szabo, Csilla" uniqKey="Szabo C" first="Csilla" last="Szabo">Csilla Szabo</name>
<affiliation><nlm:aff id="I103">University of Delaware, Newark, DE, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Offit, Kenneth" sort="Offit, Kenneth" uniqKey="Offit K" first="Kenneth" last="Offit">Kenneth Offit</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sakr, Rita" sort="Sakr, Rita" uniqKey="Sakr R" first="Rita" last="Sakr">Rita Sakr</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gaudet, Mia" sort="Gaudet, Mia" uniqKey="Gaudet M" first="Mia" last="Gaudet">Mia Gaudet</name>
<affiliation><nlm:aff id="I104">Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhatia, Jasmine" sort="Bhatia, Jasmine" uniqKey="Bhatia J" first="Jasmine" last="Bhatia">Jasmine Bhatia</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kauff, Noah" sort="Kauff, Noah" uniqKey="Kauff N" first="Noah" last="Kauff">Noah Kauff</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Singer, Christian F" sort="Singer, Christian F" uniqKey="Singer C" first="Christian F" last="Singer">Christian F. Singer</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tea, Muy Kheng" sort="Tea, Muy Kheng" uniqKey="Tea M" first="Muy-Kheng" last="Tea">Muy-Kheng Tea</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gschwantler Kaulich, Daphne" sort="Gschwantler Kaulich, Daphne" uniqKey="Gschwantler Kaulich D" first="Daphne" last="Gschwantler-Kaulich">Daphne Gschwantler-Kaulich</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fink Retter, Anneliese" sort="Fink Retter, Anneliese" uniqKey="Fink Retter A" first="Anneliese" last="Fink-Retter">Anneliese Fink-Retter</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mai, Phuong L" sort="Mai, Phuong L" uniqKey="Mai P" first="Phuong L" last="Mai">Phuong L. Mai</name>
<affiliation><nlm:aff id="I106">Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Greene, Mark H" sort="Greene, Mark H" uniqKey="Greene M" first="Mark H" last="Greene">Mark H. Greene</name>
<affiliation><nlm:aff id="I106">Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Imyanitov, Evgeny" sort="Imyanitov, Evgeny" uniqKey="Imyanitov E" first="Evgeny" last="Imyanitov">Evgeny Imyanitov</name>
<affiliation><nlm:aff id="I107">Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="O Malley, Frances P" sort="O Malley, Frances P" uniqKey="O Malley F" first="Frances P" last="O'Malley">Frances P. O'Malley</name>
<affiliation><nlm:aff id="I108">Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ozcelik, Hilmi" sort="Ozcelik, Hilmi" uniqKey="Ozcelik H" first="Hilmi" last="Ozcelik">Hilmi Ozcelik</name>
<affiliation><nlm:aff id="I109">Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Glendon, Gordon" sort="Glendon, Gordon" uniqKey="Glendon G" first="Gordon" last="Glendon">Gordon Glendon</name>
<affiliation><nlm:aff id="I110">Cancer Care Ontario, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Toland, Amanda E" sort="Toland, Amanda E" uniqKey="Toland A" first="Amanda E" last="Toland">Amanda E. Toland</name>
<affiliation><nlm:aff id="I111">Departments of Molecular Virology, Immunology and Medical Genetics and Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gerdes, Anne Marie" sort="Gerdes, Anne Marie" uniqKey="Gerdes A" first="Anne-Marie" last="Gerdes">Anne-Marie Gerdes</name>
<affiliation><nlm:aff id="I112">Clinical Genetics, Rigshospital, Copenhagen University, Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thomassen, Mads" sort="Thomassen, Mads" uniqKey="Thomassen M" first="Mads" last="Thomassen">Mads Thomassen</name>
<affiliation><nlm:aff id="I113">Clinical Genetics, Odense University Hospital, Odense, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kruse, Torben A" sort="Kruse, Torben A" uniqKey="Kruse T" first="Torben A" last="Kruse">Torben A. Kruse</name>
<affiliation><nlm:aff id="I113">Clinical Genetics, Odense University Hospital, Odense, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jensen, Uffe Birk" sort="Jensen, Uffe Birk" uniqKey="Jensen U" first="Uffe Birk" last="Jensen">Uffe Birk Jensen</name>
<affiliation><nlm:aff id="I114">Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Skytte, Anne Bine" sort="Skytte, Anne Bine" uniqKey="Skytte A" first="Anne-Bine" last="Skytte">Anne-Bine Skytte</name>
<affiliation><nlm:aff id="I115">Clinical Genetics, Vejle Hospital, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Caligo, Maria A" sort="Caligo, Maria A" uniqKey="Caligo M" first="Maria A" last="Caligo">Maria A. Caligo</name>
<affiliation><nlm:aff id="I116">Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Soller, Maria" sort="Soller, Maria" uniqKey="Soller M" first="Maria" last="Soller">Maria Soller</name>
<affiliation><nlm:aff id="I117">Department of Clinical Genetics, Lund University Hospital, Lund, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Henriksson, Karin" sort="Henriksson, Karin" uniqKey="Henriksson K" first="Karin" last="Henriksson">Karin Henriksson</name>
<affiliation><nlm:aff id="I118">Oncological Centre, Lund University Hospital, Lund, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wachenfeldt, Von Anna" sort="Wachenfeldt, Von Anna" uniqKey="Wachenfeldt V" first="Von Anna" last="Wachenfeldt">Von Anna Wachenfeldt</name>
<affiliation><nlm:aff id="I119">Department of Oncology, Karolinska University Hospital, Stockholm, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Arver, Brita" sort="Arver, Brita" uniqKey="Arver B" first="Brita" last="Arver">Brita Arver</name>
<affiliation><nlm:aff id="I119">Department of Oncology, Karolinska University Hospital, Stockholm, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stenmark Askmalm, Marie" sort="Stenmark Askmalm, Marie" uniqKey="Stenmark Askmalm M" first="Marie" last="Stenmark-Askmalm">Marie Stenmark-Askmalm</name>
<affiliation><nlm:aff id="I120">Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Karlsson, Per" sort="Karlsson, Per" uniqKey="Karlsson P" first="Per" last="Karlsson">Per Karlsson</name>
<affiliation><nlm:aff id="I121">Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ding, Yuan Chun" sort="Ding, Yuan Chun" uniqKey="Ding Y" first="Yuan Chun" last="Ding">Yuan Chun Ding</name>
<affiliation><nlm:aff id="I122">Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Neuhausen, Susan L" sort="Neuhausen, Susan L" uniqKey="Neuhausen S" first="Susan L" last="Neuhausen">Susan L. Neuhausen</name>
<affiliation><nlm:aff id="I122">Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beattie, Mary" sort="Beattie, Mary" uniqKey="Beattie M" first="Mary" last="Beattie">Mary Beattie</name>
<affiliation><nlm:aff id="I123">UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pharoah, Paul Dp" sort="Pharoah, Paul Dp" uniqKey="Pharoah P" first="Paul Dp" last="Pharoah">Paul Dp Pharoah</name>
<affiliation><nlm:aff id="I124">Department of Oncology, University of Cambridge, Cambridge, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Moysich, Kirsten B" sort="Moysich, Kirsten B" uniqKey="Moysich K" first="Kirsten B" last="Moysich">Kirsten B. Moysich</name>
<affiliation><nlm:aff id="I125">Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nathanson, Katherine L" sort="Nathanson, Katherine L" uniqKey="Nathanson K" first="Katherine L" last="Nathanson">Katherine L. Nathanson</name>
<affiliation><nlm:aff id="I4">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Karlan, Beth Y" sort="Karlan, Beth Y" uniqKey="Karlan B" first="Beth Y" last="Karlan">Beth Y. Karlan</name>
<affiliation><nlm:aff id="I126">Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gross, Jenny" sort="Gross, Jenny" uniqKey="Gross J" first="Jenny" last="Gross">Jenny Gross</name>
<affiliation><nlm:aff id="I126">Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M" last="John">Esther M. John</name>
<affiliation><nlm:aff id="I127">Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Daly, Mary B" sort="Daly, Mary B" uniqKey="Daly M" first="Mary B" last="Daly">Mary B. Daly</name>
<affiliation><nlm:aff id="I128">Fox Chase Cancer Center, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Buys, Saundra M" sort="Buys, Saundra M" uniqKey="Buys S" first="Saundra M" last="Buys">Saundra M. Buys</name>
<affiliation><nlm:aff id="I129">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name>
<affiliation><nlm:aff id="I130">Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, VIC, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L" last="Hopper">John L. Hopper</name>
<affiliation><nlm:aff id="I131">Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, VIC, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Terry, Mary Beth" sort="Terry, Mary Beth" uniqKey="Terry M" first="Mary Beth" last="Terry">Mary Beth Terry</name>
<affiliation><nlm:aff id="I132">Department of Epidemiology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chung, Wendy" sort="Chung, Wendy" uniqKey="Chung W" first="Wendy" last="Chung">Wendy Chung</name>
<affiliation><nlm:aff id="I132">Department of Epidemiology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Miron, Alexander F" sort="Miron, Alexander F" uniqKey="Miron A" first="Alexander F" last="Miron">Alexander F. Miron</name>
<affiliation><nlm:aff id="I133">Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goldgar, David" sort="Goldgar, David" uniqKey="Goldgar D" first="David" last="Goldgar">David Goldgar</name>
<affiliation><nlm:aff id="I134">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name>
<affiliation><nlm:aff id="I10">Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F" last="Easton">Douglas F. Easton</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L" last="Andrulis">Irene L. Andrulis</name>
<affiliation><nlm:aff id="I135">Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada; Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Antoniou, Antonis C" sort="Antoniou, Antonis C" uniqKey="Antoniou A" first="Antonis C" last="Antoniou">Antonis C. Antoniou</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">22053997</idno>
<idno type="pmc">3326552</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326552</idno>
<idno type="RBID">PMC:3326552</idno>
<idno type="doi">10.1186/bcr3052</idno>
<date when="2011">2011</date>
<idno type="wicri:Area/Pmc/Corpus">002357</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002357</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Common breast cancer susceptibility alleles are associated with tumour subtypes in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers: results from the Consortium of Investigators of Modifiers of <italic>BRCA1/2</italic>
</title>
<author><name sortKey="Mulligan, Anna Marie" sort="Mulligan, Anna Marie" uniqKey="Mulligan A" first="Anna Marie" last="Mulligan">Anna Marie Mulligan</name>
<affiliation><nlm:aff id="I1">Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J" last="Couch">Fergus J. Couch</name>
<affiliation><nlm:aff id="I2">Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barrowdale, Daniel" sort="Barrowdale, Daniel" uniqKey="Barrowdale D" first="Daniel" last="Barrowdale">Daniel Barrowdale</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Domchek, Susan M" sort="Domchek, Susan M" uniqKey="Domchek S" first="Susan M" last="Domchek">Susan M. Domchek</name>
<affiliation><nlm:aff id="I4">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eccles, Diana" sort="Eccles, Diana" uniqKey="Eccles D" first="Diana" last="Eccles">Diana Eccles</name>
<affiliation><nlm:aff id="I5">Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nevanlinna, Heli" sort="Nevanlinna, Heli" uniqKey="Nevanlinna H" first="Heli" last="Nevanlinna">Heli Nevanlinna</name>
<affiliation><nlm:aff id="I6">Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ramus, Susan J" sort="Ramus, Susan J" uniqKey="Ramus S" first="Susan J" last="Ramus">Susan J. Ramus</name>
<affiliation><nlm:aff id="I7">Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N Soto Street, Los Angeles, CA 90089-9237, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Robson, Mark" sort="Robson, Mark" uniqKey="Robson M" first="Mark" last="Robson">Mark Robson</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sherman, Mark" sort="Sherman, Mark" uniqKey="Sherman M" first="Mark" last="Sherman">Mark Sherman</name>
<affiliation><nlm:aff id="I9">National Cancer Institute, Division of Cancer Epidemiology and Genetics, Hormonal and Reproductive Epidemiology Branch, 6120 Executive Blvd., Rockville, MD 20852, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name>
<affiliation><nlm:aff id="I10">Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name>
<affiliation><nlm:aff id="I11">Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Andrew" sort="Lee, Andrew" uniqKey="Lee A" first="Andrew" last="Lee">Andrew Lee</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Healey, Sue" sort="Healey, Sue" uniqKey="Healey S" first="Sue" last="Healey">Sue Healey</name>
<affiliation><nlm:aff id="I10">Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M" last="Sinilnikova">Olga M. Sinilnikova</name>
<affiliation><nlm:aff id="I12">Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="I13">INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Janavicius, Ramunas" sort="Janavicius, Ramunas" uniqKey="Janavicius R" first="Ramunas" last="Janavicius">Ramunas Janavicius</name>
<affiliation><nlm:aff id="I14">Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, Santariskiu st 2, LT-08661 Vilnius and State Research Institute Innovative Medicine Center, Zygimantu st. 9, LT-01102 Vilnius, Lithuania</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hansen, Thomas Vo" sort="Hansen, Thomas Vo" uniqKey="Hansen T" first="Thomas Vo" last="Hansen">Thomas Vo Hansen</name>
<affiliation><nlm:aff id="I15">Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nielsen, Finn C" sort="Nielsen, Finn C" uniqKey="Nielsen F" first="Finn C" last="Nielsen">Finn C. Nielsen</name>
<affiliation><nlm:aff id="I15">Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ejlertsen, Bent" sort="Ejlertsen, Bent" uniqKey="Ejlertsen B" first="Bent" last="Ejlertsen">Bent Ejlertsen</name>
<affiliation><nlm:aff id="I16">Department of Oncology, Rigshospitalet Bldg. 4262, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Osorio, Ana" sort="Osorio, Ana" uniqKey="Osorio A" first="Ana" last="Osorio">Ana Osorio</name>
<affiliation><nlm:aff id="I17">Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mu Oz Repeto, Ivan" sort="Mu Oz Repeto, Ivan" uniqKey="Mu Oz Repeto I" first="Iván" last="Mu Oz-Repeto">Iván Mu Oz-Repeto</name>
<affiliation><nlm:aff id="I17">Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Duran, Mercedes" sort="Duran, Mercedes" uniqKey="Duran M" first="Mercedes" last="Durán">Mercedes Durán</name>
<affiliation><nlm:aff id="I18">Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), C/Sanz y Forés, N° 3, Valladolid, 47003, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Godino, Javier" sort="Godino, Javier" uniqKey="Godino J" first="Javier" last="Godino">Javier Godino</name>
<affiliation><nlm:aff id="I19">Instituto de investigación sanitaria de Aragón (IIS), Hospital clinico Universitario "Lozano Blesa", San Juan Bosco 15, Zaragoza, 50009, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pertesi, Maroulio" sort="Pertesi, Maroulio" uniqKey="Pertesi M" first="Maroulio" last="Pertesi">Maroulio Pertesi</name>
<affiliation><nlm:aff id="I20">Molecular Diagnostics Laboratory, IRRP, National Center for Scientific Research Demokritos, Patriarchou Gregoriou E' & Neapoleos Str, Ag. Paraskevi 15310, Athens, Greece</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benítez">Javier Benítez</name>
<affiliation><nlm:aff id="I21">Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Peterlongo, Paolo" sort="Peterlongo, Paolo" uniqKey="Peterlongo P" first="Paolo" last="Peterlongo">Paolo Peterlongo</name>
<affiliation><nlm:aff id="I22">Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, 20133 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, 20139 Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Manoukian, Siranoush" sort="Manoukian, Siranoush" uniqKey="Manoukian S" first="Siranoush" last="Manoukian">Siranoush Manoukian</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Peissel, Bernard" sort="Peissel, Bernard" uniqKey="Peissel B" first="Bernard" last="Peissel">Bernard Peissel</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zaffaroni, Daniela" sort="Zaffaroni, Daniela" uniqKey="Zaffaroni D" first="Daniela" last="Zaffaroni">Daniela Zaffaroni</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cattaneo, Elisa" sort="Cattaneo, Elisa" uniqKey="Cattaneo E" first="Elisa" last="Cattaneo">Elisa Cattaneo</name>
<affiliation><nlm:aff id="I23">Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bonanni, Bernardo" sort="Bonanni, Bernardo" uniqKey="Bonanni B" first="Bernardo" last="Bonanni">Bernardo Bonanni</name>
<affiliation><nlm:aff id="I24">Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, via Ripamonti 435, Milan, 20141, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Viel, Alessandra" sort="Viel, Alessandra" uniqKey="Viel A" first="Alessandra" last="Viel">Alessandra Viel</name>
<affiliation><nlm:aff id="I25">Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pasini, Barbara" sort="Pasini, Barbara" uniqKey="Pasini B" first="Barbara" last="Pasini">Barbara Pasini</name>
<affiliation><nlm:aff id="I26">Department of Genetics, Biology and BiochemIstry, University of Turin, Turin, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Papi, Laura" sort="Papi, Laura" uniqKey="Papi L" first="Laura" last="Papi">Laura Papi</name>
<affiliation><nlm:aff id="I27">Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Firenze, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ottini, Laura" sort="Ottini, Laura" uniqKey="Ottini L" first="Laura" last="Ottini">Laura Ottini</name>
<affiliation><nlm:aff id="I28">Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Savarese, Antonella" sort="Savarese, Antonella" uniqKey="Savarese A" first="Antonella" last="Savarese">Antonella Savarese</name>
<affiliation><nlm:aff id="I29">Division of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bernard, Loris" sort="Bernard, Loris" uniqKey="Bernard L" first="Loris" last="Bernard">Loris Bernard</name>
<affiliation><nlm:aff id="I30">Department of Experimental Oncology, Istituto Europeo di Oncologia. Milan, Italy; Consortium for Genomics Technology (Cogentech), Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Radice, Paolo" sort="Radice, Paolo" uniqKey="Radice P" first="Paolo" last="Radice">Paolo Radice</name>
<affiliation><nlm:aff id="I22">Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, 20133 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, 20139 Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name>
<affiliation><nlm:aff id="I31">Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Verheus, Martijn" sort="Verheus, Martijn" uniqKey="Verheus M" first="Martijn" last="Verheus">Martijn Verheus</name>
<affiliation><nlm:aff id="I32">Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meijers Heijboer, Hanne Ej" sort="Meijers Heijboer, Hanne Ej" uniqKey="Meijers Heijboer H" first="Hanne Ej" last="Meijers-Heijboer">Hanne Ej Meijers-Heijboer</name>
<affiliation><nlm:aff id="I33">Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wijnen, Juul" sort="Wijnen, Juul" uniqKey="Wijnen J" first="Juul" last="Wijnen">Juul Wijnen</name>
<affiliation><nlm:aff id="I34">Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="G Mez Garcia, Encarna B" sort="G Mez Garcia, Encarna B" uniqKey="G Mez Garcia E" first="Encarna B" last="G Mez García">Encarna B. G Mez García</name>
<affiliation><nlm:aff id="I35">Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nelen, Marcel R" sort="Nelen, Marcel R" uniqKey="Nelen M" first="Marcel R" last="Nelen">Marcel R. Nelen</name>
<affiliation><nlm:aff id="I36">Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kets, C Marleen" sort="Kets, C Marleen" uniqKey="Kets C" first="C Marleen" last="Kets">C Marleen Kets</name>
<affiliation><nlm:aff id="I37">Department of Human Genetics 836, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seynaeve, Caroline" sort="Seynaeve, Caroline" uniqKey="Seynaeve C" first="Caroline" last="Seynaeve">Caroline Seynaeve</name>
<affiliation><nlm:aff id="I38">Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tilanus Linthorst, Madeleine Ma" sort="Tilanus Linthorst, Madeleine Ma" uniqKey="Tilanus Linthorst M" first="Madeleine Ma" last="Tilanus-Linthorst">Madeleine Ma Tilanus-Linthorst</name>
<affiliation><nlm:aff id="I39">Department of Surgical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Van Der Luijt, Rob B" sort="Van Der Luijt, Rob B" uniqKey="Van Der Luijt R" first="Rob B" last="Van Der Luijt">Rob B. Van Der Luijt</name>
<affiliation><nlm:aff id="I40">Department of Medical Genetics, University Medical Center Utrecht, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Os, Theo Van" sort="Os, Theo Van" uniqKey="Os T" first="Theo Van" last="Os">Theo Van Os</name>
<affiliation><nlm:aff id="I41">Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rookus, Matti" sort="Rookus, Matti" uniqKey="Rookus M" first="Matti" last="Rookus">Matti Rookus</name>
<affiliation><nlm:aff id="I32">Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Frost, Debra" sort="Frost, Debra" uniqKey="Frost D" first="Debra" last="Frost">Debra Frost</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jones, J Louise" sort="Jones, J Louise" uniqKey="Jones J" first="J Louise" last="Jones">J Louise Jones</name>
<affiliation><nlm:aff id="I42">Barts Cancer Institute, Queen Mary University of London, Centre for Tumour Biology, Charterhouse Square, London, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Evans, D Gareth" sort="Evans, D Gareth" uniqKey="Evans D" first="D Gareth" last="Evans">D Gareth Evans</name>
<affiliation><nlm:aff id="I43">Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lalloo, Fiona" sort="Lalloo, Fiona" uniqKey="Lalloo F" first="Fiona" last="Lalloo">Fiona Lalloo</name>
<affiliation><nlm:aff id="I43">Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eeles, Ros" sort="Eeles, Ros" uniqKey="Eeles R" first="Ros" last="Eeles">Ros Eeles</name>
<affiliation><nlm:aff id="I44">Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Izatt, Louise" sort="Izatt, Louise" uniqKey="Izatt L" first="Louise" last="Izatt">Louise Izatt</name>
<affiliation><nlm:aff id="I45">Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Adlard, Julian" sort="Adlard, Julian" uniqKey="Adlard J" first="Julian" last="Adlard">Julian Adlard</name>
<affiliation><nlm:aff id="I46">Yorkshire Regional Genetics Service, Leeds, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Davidson, Rosemarie" sort="Davidson, Rosemarie" uniqKey="Davidson R" first="Rosemarie" last="Davidson">Rosemarie Davidson</name>
<affiliation><nlm:aff id="I47">Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cook, Jackie" sort="Cook, Jackie" uniqKey="Cook J" first="Jackie" last="Cook">Jackie Cook</name>
<affiliation><nlm:aff id="I48">Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Donaldson, Alan" sort="Donaldson, Alan" uniqKey="Donaldson A" first="Alan" last="Donaldson">Alan Donaldson</name>
<affiliation><nlm:aff id="I49">Clinical Genetics Department, St Michael's Hospital, Bristol, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dorkins, Huw" sort="Dorkins, Huw" uniqKey="Dorkins H" first="Huw" last="Dorkins">Huw Dorkins</name>
<affiliation><nlm:aff id="I50">North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gregory, Helen" sort="Gregory, Helen" uniqKey="Gregory H" first="Helen" last="Gregory">Helen Gregory</name>
<affiliation><nlm:aff id="I51">North of Scotland Regional Genetics Service, NHS Grampian and University of Aberdeen, Foresterhill, Aberdeen, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eason, Jacqueline" sort="Eason, Jacqueline" uniqKey="Eason J" first="Jacqueline" last="Eason">Jacqueline Eason</name>
<affiliation><nlm:aff id="I52">Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Houghton, Catherine" sort="Houghton, Catherine" uniqKey="Houghton C" first="Catherine" last="Houghton">Catherine Houghton</name>
<affiliation><nlm:aff id="I53">Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barwell, Julian" sort="Barwell, Julian" uniqKey="Barwell J" first="Julian" last="Barwell">Julian Barwell</name>
<affiliation><nlm:aff id="I54">Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Side, Lucy E" sort="Side, Lucy E" uniqKey="Side L" first="Lucy E" last="Side">Lucy E. Side</name>
<affiliation><nlm:aff id="I55">North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mccann, Emma" sort="Mccann, Emma" uniqKey="Mccann E" first="Emma" last="Mccann">Emma Mccann</name>
<affiliation><nlm:aff id="I56">All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Murray, Alex" sort="Murray, Alex" uniqKey="Murray A" first="Alex" last="Murray">Alex Murray</name>
<affiliation><nlm:aff id="I57">All Wales Medical Genetics Services, Singleton Hospital, Swansea, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Peock, Susan" sort="Peock, Susan" uniqKey="Peock S" first="Susan" last="Peock">Susan Peock</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Godwin, Andrew K" sort="Godwin, Andrew K" uniqKey="Godwin A" first="Andrew K" last="Godwin">Andrew K. Godwin</name>
<affiliation><nlm:aff id="I58">Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K" last="Schmutzler">Rita K. Schmutzler</name>
<affiliation><nlm:aff id="I11">Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rhiem, Kerstin" sort="Rhiem, Kerstin" uniqKey="Rhiem K" first="Kerstin" last="Rhiem">Kerstin Rhiem</name>
<affiliation><nlm:aff id="I11">Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Engel, Christoph" sort="Engel, Christoph" uniqKey="Engel C" first="Christoph" last="Engel">Christoph Engel</name>
<affiliation><nlm:aff id="I59">Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name>
<affiliation><nlm:aff id="I60">Department of Gynaecology and Obstetrics, Division of Tumour Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ruehl, Ina" sort="Ruehl, Ina" uniqKey="Ruehl I" first="Ina" last="Ruehl">Ina Ruehl</name>
<affiliation><nlm:aff id="I61">Department of Gynaecology and Obstetrics, Ludwig-Maximillians University, Munich, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Arnold, Norbert" sort="Arnold, Norbert" uniqKey="Arnold N" first="Norbert" last="Arnold">Norbert Arnold</name>
<affiliation><nlm:aff id="I62">Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Christian-Albrechts University, Kiel, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Niederacher, Dieter" sort="Niederacher, Dieter" uniqKey="Niederacher D" first="Dieter" last="Niederacher">Dieter Niederacher</name>
<affiliation><nlm:aff id="I63">Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sutter, Christian" sort="Sutter, Christian" uniqKey="Sutter C" first="Christian" last="Sutter">Christian Sutter</name>
<affiliation><nlm:aff id="I64">Institute of Human Genetics, Department of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Deissler, Helmut" sort="Deissler, Helmut" uniqKey="Deissler H" first="Helmut" last="Deissler">Helmut Deissler</name>
<affiliation><nlm:aff id="I65">Department of Gynaecology and Obstetrics, University Hospital, Ulm, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gadzicki, Dorothea" sort="Gadzicki, Dorothea" uniqKey="Gadzicki D" first="Dorothea" last="Gadzicki">Dorothea Gadzicki</name>
<affiliation><nlm:aff id="I66">Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kast, Karin" sort="Kast, Karin" uniqKey="Kast K" first="Karin" last="Kast">Karin Kast</name>
<affiliation><nlm:aff id="I67">Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University, Dresden, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Preisler Adams, Sabine" sort="Preisler Adams, Sabine" uniqKey="Preisler Adams S" first="Sabine" last="Preisler-Adams">Sabine Preisler-Adams</name>
<affiliation><nlm:aff id="I68">Institute of Human Genetics, University of Münster, Münster, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Varon Mateeva, Raymonda" sort="Varon Mateeva, Raymonda" uniqKey="Varon Mateeva R" first="Raymonda" last="Varon-Mateeva">Raymonda Varon-Mateeva</name>
<affiliation><nlm:aff id="I69">Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schoenbuchner, Ines" sort="Schoenbuchner, Ines" uniqKey="Schoenbuchner I" first="Ines" last="Schoenbuchner">Ines Schoenbuchner</name>
<affiliation><nlm:aff id="I70">Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fiebig, Britta" sort="Fiebig, Britta" uniqKey="Fiebig B" first="Britta" last="Fiebig">Britta Fiebig</name>
<affiliation><nlm:aff id="I71">Institute of Human Genetics, University Regensburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Heinritz, Wolfram" sort="Heinritz, Wolfram" uniqKey="Heinritz W" first="Wolfram" last="Heinritz">Wolfram Heinritz</name>
<affiliation><nlm:aff id="I72">Institute of Human Genetics, University Leipzig, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sch Fer, Dieter" sort="Sch Fer, Dieter" uniqKey="Sch Fer D" first="Dieter" last="Sch Fer">Dieter Sch Fer</name>
<affiliation><nlm:aff id="I73">Institute of Human Genetics, University Hospital, Frankfurt a.M., Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gevensleben, Heidrun" sort="Gevensleben, Heidrun" uniqKey="Gevensleben H" first="Heidrun" last="Gevensleben">Heidrun Gevensleben</name>
<affiliation><nlm:aff id="I74">Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Caux Moncoutier, Virginie" sort="Caux Moncoutier, Virginie" uniqKey="Caux Moncoutier V" first="Virginie" last="Caux-Moncoutier">Virginie Caux-Moncoutier</name>
<affiliation><nlm:aff id="I75">Service de Génétique Oncologique, Institut Curie, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fassy Colcombet, Marion" sort="Fassy Colcombet, Marion" uniqKey="Fassy Colcombet M" first="Marion" last="Fassy-Colcombet">Marion Fassy-Colcombet</name>
<affiliation><nlm:aff id="I75">Service de Génétique Oncologique, Institut Curie, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cornelis, Francois" sort="Cornelis, Francois" uniqKey="Cornelis F" first="François" last="Cornelis">François Cornelis</name>
<affiliation><nlm:aff id="I76">Genetic Unit, Avicenne Hospital, Assitance Publique-Hôpitaux de Paris, Paris, France; Sud-Francilien Hospital, Evry-Corbeil, France; University Hospital, Clermont-Ferrand, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mazoyer, Sylvie" sort="Mazoyer, Sylvie" uniqKey="Mazoyer S" first="Sylvie" last="Mazoyer">Sylvie Mazoyer</name>
<affiliation><nlm:aff id="I13">INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Leone, Melanie" sort="Leone, Melanie" uniqKey="Leone M" first="Mélanie" last="Léoné">Mélanie Léoné</name>
<affiliation><nlm:aff id="I12">Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Boutry Kryza, Nadia" sort="Boutry Kryza, Nadia" uniqKey="Boutry Kryza N" first="Nadia" last="Boutry-Kryza">Nadia Boutry-Kryza</name>
<affiliation><nlm:aff id="I12">Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hardouin, Agnes" sort="Hardouin, Agnes" uniqKey="Hardouin A" first="Agnès" last="Hardouin">Agnès Hardouin</name>
<affiliation><nlm:aff id="I77">Centre François Baclesse, Caen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Berthet, Pascaline" sort="Berthet, Pascaline" uniqKey="Berthet P" first="Pascaline" last="Berthet">Pascaline Berthet</name>
<affiliation><nlm:aff id="I77">Centre François Baclesse, Caen, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Muller, Daniele" sort="Muller, Daniele" uniqKey="Muller D" first="Danièle" last="Muller">Danièle Muller</name>
<affiliation><nlm:aff id="I78">Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fricker, Jean Pierre" sort="Fricker, Jean Pierre" uniqKey="Fricker J" first="Jean-Pierre" last="Fricker">Jean-Pierre Fricker</name>
<affiliation><nlm:aff id="I78">Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mortemousque, Isabelle" sort="Mortemousque, Isabelle" uniqKey="Mortemousque I" first="Isabelle" last="Mortemousque">Isabelle Mortemousque</name>
<affiliation><nlm:aff id="I79">Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pujol, Pascal" sort="Pujol, Pascal" uniqKey="Pujol P" first="Pascal" last="Pujol">Pascal Pujol</name>
<affiliation><nlm:aff id="I80">Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Coupier, Isabelle" sort="Coupier, Isabelle" uniqKey="Coupier I" first="Isabelle" last="Coupier">Isabelle Coupier</name>
<affiliation><nlm:aff id="I80">Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lebrun, Marine" sort="Lebrun, Marine" uniqKey="Lebrun M" first="Marine" last="Lebrun">Marine Lebrun</name>
<affiliation><nlm:aff id="I81">Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kientz, Caroline" sort="Kientz, Caroline" uniqKey="Kientz C" first="Caroline" last="Kientz">Caroline Kientz</name>
<affiliation><nlm:aff id="I81">Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Longy, Michel" sort="Longy, Michel" uniqKey="Longy M" first="Michel" last="Longy">Michel Longy</name>
<affiliation><nlm:aff id="I82">Cancer Genetics Unit, INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sevenet, Nicolas" sort="Sevenet, Nicolas" uniqKey="Sevenet N" first="Nicolas" last="Sevenet">Nicolas Sevenet</name>
<affiliation><nlm:aff id="I82">Cancer Genetics Unit, INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stoppa Lyonnet, Dominique" sort="Stoppa Lyonnet, Dominique" uniqKey="Stoppa Lyonnet D" first="Dominique" last="Stoppa-Lyonnet">Dominique Stoppa-Lyonnet</name>
<affiliation><nlm:aff id="I75">Service de Génétique Oncologique, Institut Curie, Paris, France</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="I83">Unité INSERM U830, Institut Curie, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Isaacs, Claudine" sort="Isaacs, Claudine" uniqKey="Isaacs C" first="Claudine" last="Isaacs">Claudine Isaacs</name>
<affiliation><nlm:aff id="I84">Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Caldes, Trinidad" sort="Caldes, Trinidad" uniqKey="Caldes T" first="Trinidad" last="Caldes">Trinidad Caldes</name>
<affiliation><nlm:aff id="I85">Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="De La Hoya, Miguel" sort="De La Hoya, Miguel" uniqKey="De La Hoya M" first="Miguel" last="De La Hoya">Miguel De La Hoya</name>
<affiliation><nlm:aff id="I85">Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Heikkinen, Tuomas" sort="Heikkinen, Tuomas" uniqKey="Heikkinen T" first="Tuomas" last="Heikkinen">Tuomas Heikkinen</name>
<affiliation><nlm:aff id="I6">Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Aittom Ki, Kristiina" sort="Aittom Ki, Kristiina" uniqKey="Aittom Ki K" first="Kristiina" last="Aittom Ki">Kristiina Aittom Ki</name>
<affiliation><nlm:aff id="I86">Department of Clinical Genetics, Helsinki University Central Hospital, Meilahdentie 2, 00290 Helsinki, Finland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Blanco, Ignacio" sort="Blanco, Ignacio" uniqKey="Blanco I" first="Ignacio" last="Blanco">Ignacio Blanco</name>
<affiliation><nlm:aff id="I87">Hereditary Cancer Program, Institut Català d'Oncologia, Hospital Duran i Reynals - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lazaro, Conxi" sort="Lazaro, Conxi" uniqKey="Lazaro C" first="Conxi" last="Lazaro">Conxi Lazaro</name>
<affiliation><nlm:aff id="I87">Hereditary Cancer Program, Institut Català d'Oncologia, Hospital Duran i Reynals - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barkardottir, Rosa B" sort="Barkardottir, Rosa B" uniqKey="Barkardottir R" first="Rosa B" last="Barkardottir">Rosa B. Barkardottir</name>
<affiliation><nlm:aff id="I88">Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland, Faculty of Medicine, University of Iceland, Reykjavik, Iceland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Soucy, Penny" sort="Soucy, Penny" uniqKey="Soucy P" first="Penny" last="Soucy">Penny Soucy</name>
<affiliation><nlm:aff id="I89">Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dumont, Martine" sort="Dumont, Martine" uniqKey="Dumont M" first="Martine" last="Dumont">Martine Dumont</name>
<affiliation><nlm:aff id="I89">Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name>
<affiliation><nlm:aff id="I90">Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada; Canada Research Chair in Oncogenetics, Department of Molecular Medicine, Faculty of Medicine, Laval University, QC, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Montagna, Marco" sort="Montagna, Marco" uniqKey="Montagna M" first="Marco" last="Montagna">Marco Montagna</name>
<affiliation><nlm:aff id="I91">Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tognazzo, Silvia" sort="Tognazzo, Silvia" uniqKey="Tognazzo S" first="Silvia" last="Tognazzo">Silvia Tognazzo</name>
<affiliation><nlm:aff id="I91">Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="D Andrea, Emma" sort="D Andrea, Emma" uniqKey="D Andrea E" first="Emma" last="D'Andrea">Emma D'Andrea</name>
<affiliation><nlm:aff id="I92">Department of Oncology and Surgical Sciences, University of Padua and Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fox, Stephen" sort="Fox, Stephen" uniqKey="Fox S" first="Stephen" last="Fox">Stephen Fox</name>
<affiliation><nlm:aff id="I93">Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yan, Max" sort="Yan, Max" uniqKey="Yan M" first="Max" last="Yan">Max Yan</name>
<affiliation><nlm:aff id="I94">Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rebbeck, Tim" sort="Rebbeck, Tim" uniqKey="Rebbeck T" first="Tim" last="Rebbeck">Tim Rebbeck</name>
<affiliation><nlm:aff id="I95">Abramson Cancer Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olopade, Olufunmilayo I" sort="Olopade, Olufunmilayo I" uniqKey="Olopade O" first="Olufunmilayo I" last="Olopade">Olufunmilayo I. Olopade</name>
<affiliation><nlm:aff id="I96">University of Chicago, Chicago, IL, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Weitzel, Jeffrey N" sort="Weitzel, Jeffrey N" uniqKey="Weitzel J" first="Jeffrey N" last="Weitzel">Jeffrey N. Weitzel</name>
<affiliation><nlm:aff id="I97">City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lynch, Henry T" sort="Lynch, Henry T" uniqKey="Lynch H" first="Henry T" last="Lynch">Henry T. Lynch</name>
<affiliation><nlm:aff id="I98">Departments of Medicine, and Preventive Medicine and Public Health, Creighton University, Omaha, NE, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ganz, Patricia A" sort="Ganz, Patricia A" uniqKey="Ganz P" first="Patricia A" last="Ganz">Patricia A. Ganz</name>
<affiliation><nlm:aff id="I99">Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tomlinson, Gail E" sort="Tomlinson, Gail E" uniqKey="Tomlinson G" first="Gail E" last="Tomlinson">Gail E. Tomlinson</name>
<affiliation><nlm:aff id="I100">Department of Internal Medicine and Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX; USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wang, Xianshu" sort="Wang, Xianshu" uniqKey="Wang X" first="Xianshu" last="Wang">Xianshu Wang</name>
<affiliation><nlm:aff id="I2">Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fredericksen, Zachary" sort="Fredericksen, Zachary" uniqKey="Fredericksen Z" first="Zachary" last="Fredericksen">Zachary Fredericksen</name>
<affiliation><nlm:aff id="I101">Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pankratz, Vernon S" sort="Pankratz, Vernon S" uniqKey="Pankratz V" first="Vernon S" last="Pankratz">Vernon S. Pankratz</name>
<affiliation><nlm:aff id="I101">Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lindor, Noralane M" sort="Lindor, Noralane M" uniqKey="Lindor N" first="Noralane M" last="Lindor">Noralane M. Lindor</name>
<affiliation><nlm:aff id="I102">Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Szabo, Csilla" sort="Szabo, Csilla" uniqKey="Szabo C" first="Csilla" last="Szabo">Csilla Szabo</name>
<affiliation><nlm:aff id="I103">University of Delaware, Newark, DE, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Offit, Kenneth" sort="Offit, Kenneth" uniqKey="Offit K" first="Kenneth" last="Offit">Kenneth Offit</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sakr, Rita" sort="Sakr, Rita" uniqKey="Sakr R" first="Rita" last="Sakr">Rita Sakr</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gaudet, Mia" sort="Gaudet, Mia" uniqKey="Gaudet M" first="Mia" last="Gaudet">Mia Gaudet</name>
<affiliation><nlm:aff id="I104">Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhatia, Jasmine" sort="Bhatia, Jasmine" uniqKey="Bhatia J" first="Jasmine" last="Bhatia">Jasmine Bhatia</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kauff, Noah" sort="Kauff, Noah" uniqKey="Kauff N" first="Noah" last="Kauff">Noah Kauff</name>
<affiliation><nlm:aff id="I8">Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Singer, Christian F" sort="Singer, Christian F" uniqKey="Singer C" first="Christian F" last="Singer">Christian F. Singer</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tea, Muy Kheng" sort="Tea, Muy Kheng" uniqKey="Tea M" first="Muy-Kheng" last="Tea">Muy-Kheng Tea</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gschwantler Kaulich, Daphne" sort="Gschwantler Kaulich, Daphne" uniqKey="Gschwantler Kaulich D" first="Daphne" last="Gschwantler-Kaulich">Daphne Gschwantler-Kaulich</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fink Retter, Anneliese" sort="Fink Retter, Anneliese" uniqKey="Fink Retter A" first="Anneliese" last="Fink-Retter">Anneliese Fink-Retter</name>
<affiliation><nlm:aff id="I105">Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mai, Phuong L" sort="Mai, Phuong L" uniqKey="Mai P" first="Phuong L" last="Mai">Phuong L. Mai</name>
<affiliation><nlm:aff id="I106">Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Greene, Mark H" sort="Greene, Mark H" uniqKey="Greene M" first="Mark H" last="Greene">Mark H. Greene</name>
<affiliation><nlm:aff id="I106">Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Imyanitov, Evgeny" sort="Imyanitov, Evgeny" uniqKey="Imyanitov E" first="Evgeny" last="Imyanitov">Evgeny Imyanitov</name>
<affiliation><nlm:aff id="I107">Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="O Malley, Frances P" sort="O Malley, Frances P" uniqKey="O Malley F" first="Frances P" last="O'Malley">Frances P. O'Malley</name>
<affiliation><nlm:aff id="I108">Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ozcelik, Hilmi" sort="Ozcelik, Hilmi" uniqKey="Ozcelik H" first="Hilmi" last="Ozcelik">Hilmi Ozcelik</name>
<affiliation><nlm:aff id="I109">Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Glendon, Gordon" sort="Glendon, Gordon" uniqKey="Glendon G" first="Gordon" last="Glendon">Gordon Glendon</name>
<affiliation><nlm:aff id="I110">Cancer Care Ontario, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Toland, Amanda E" sort="Toland, Amanda E" uniqKey="Toland A" first="Amanda E" last="Toland">Amanda E. Toland</name>
<affiliation><nlm:aff id="I111">Departments of Molecular Virology, Immunology and Medical Genetics and Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gerdes, Anne Marie" sort="Gerdes, Anne Marie" uniqKey="Gerdes A" first="Anne-Marie" last="Gerdes">Anne-Marie Gerdes</name>
<affiliation><nlm:aff id="I112">Clinical Genetics, Rigshospital, Copenhagen University, Copenhagen, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thomassen, Mads" sort="Thomassen, Mads" uniqKey="Thomassen M" first="Mads" last="Thomassen">Mads Thomassen</name>
<affiliation><nlm:aff id="I113">Clinical Genetics, Odense University Hospital, Odense, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kruse, Torben A" sort="Kruse, Torben A" uniqKey="Kruse T" first="Torben A" last="Kruse">Torben A. Kruse</name>
<affiliation><nlm:aff id="I113">Clinical Genetics, Odense University Hospital, Odense, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jensen, Uffe Birk" sort="Jensen, Uffe Birk" uniqKey="Jensen U" first="Uffe Birk" last="Jensen">Uffe Birk Jensen</name>
<affiliation><nlm:aff id="I114">Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Skytte, Anne Bine" sort="Skytte, Anne Bine" uniqKey="Skytte A" first="Anne-Bine" last="Skytte">Anne-Bine Skytte</name>
<affiliation><nlm:aff id="I115">Clinical Genetics, Vejle Hospital, Denmark</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Caligo, Maria A" sort="Caligo, Maria A" uniqKey="Caligo M" first="Maria A" last="Caligo">Maria A. Caligo</name>
<affiliation><nlm:aff id="I116">Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Soller, Maria" sort="Soller, Maria" uniqKey="Soller M" first="Maria" last="Soller">Maria Soller</name>
<affiliation><nlm:aff id="I117">Department of Clinical Genetics, Lund University Hospital, Lund, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Henriksson, Karin" sort="Henriksson, Karin" uniqKey="Henriksson K" first="Karin" last="Henriksson">Karin Henriksson</name>
<affiliation><nlm:aff id="I118">Oncological Centre, Lund University Hospital, Lund, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wachenfeldt, Von Anna" sort="Wachenfeldt, Von Anna" uniqKey="Wachenfeldt V" first="Von Anna" last="Wachenfeldt">Von Anna Wachenfeldt</name>
<affiliation><nlm:aff id="I119">Department of Oncology, Karolinska University Hospital, Stockholm, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Arver, Brita" sort="Arver, Brita" uniqKey="Arver B" first="Brita" last="Arver">Brita Arver</name>
<affiliation><nlm:aff id="I119">Department of Oncology, Karolinska University Hospital, Stockholm, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stenmark Askmalm, Marie" sort="Stenmark Askmalm, Marie" uniqKey="Stenmark Askmalm M" first="Marie" last="Stenmark-Askmalm">Marie Stenmark-Askmalm</name>
<affiliation><nlm:aff id="I120">Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Karlsson, Per" sort="Karlsson, Per" uniqKey="Karlsson P" first="Per" last="Karlsson">Per Karlsson</name>
<affiliation><nlm:aff id="I121">Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ding, Yuan Chun" sort="Ding, Yuan Chun" uniqKey="Ding Y" first="Yuan Chun" last="Ding">Yuan Chun Ding</name>
<affiliation><nlm:aff id="I122">Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Neuhausen, Susan L" sort="Neuhausen, Susan L" uniqKey="Neuhausen S" first="Susan L" last="Neuhausen">Susan L. Neuhausen</name>
<affiliation><nlm:aff id="I122">Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beattie, Mary" sort="Beattie, Mary" uniqKey="Beattie M" first="Mary" last="Beattie">Mary Beattie</name>
<affiliation><nlm:aff id="I123">UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pharoah, Paul Dp" sort="Pharoah, Paul Dp" uniqKey="Pharoah P" first="Paul Dp" last="Pharoah">Paul Dp Pharoah</name>
<affiliation><nlm:aff id="I124">Department of Oncology, University of Cambridge, Cambridge, UK</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Moysich, Kirsten B" sort="Moysich, Kirsten B" uniqKey="Moysich K" first="Kirsten B" last="Moysich">Kirsten B. Moysich</name>
<affiliation><nlm:aff id="I125">Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nathanson, Katherine L" sort="Nathanson, Katherine L" uniqKey="Nathanson K" first="Katherine L" last="Nathanson">Katherine L. Nathanson</name>
<affiliation><nlm:aff id="I4">Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Karlan, Beth Y" sort="Karlan, Beth Y" uniqKey="Karlan B" first="Beth Y" last="Karlan">Beth Y. Karlan</name>
<affiliation><nlm:aff id="I126">Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gross, Jenny" sort="Gross, Jenny" uniqKey="Gross J" first="Jenny" last="Gross">Jenny Gross</name>
<affiliation><nlm:aff id="I126">Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M" last="John">Esther M. John</name>
<affiliation><nlm:aff id="I127">Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Daly, Mary B" sort="Daly, Mary B" uniqKey="Daly M" first="Mary B" last="Daly">Mary B. Daly</name>
<affiliation><nlm:aff id="I128">Fox Chase Cancer Center, Philadelphia, PA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Buys, Saundra M" sort="Buys, Saundra M" uniqKey="Buys S" first="Saundra M" last="Buys">Saundra M. Buys</name>
<affiliation><nlm:aff id="I129">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name>
<affiliation><nlm:aff id="I130">Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, VIC, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L" last="Hopper">John L. Hopper</name>
<affiliation><nlm:aff id="I131">Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, VIC, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Terry, Mary Beth" sort="Terry, Mary Beth" uniqKey="Terry M" first="Mary Beth" last="Terry">Mary Beth Terry</name>
<affiliation><nlm:aff id="I132">Department of Epidemiology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chung, Wendy" sort="Chung, Wendy" uniqKey="Chung W" first="Wendy" last="Chung">Wendy Chung</name>
<affiliation><nlm:aff id="I132">Department of Epidemiology, Columbia University, New York, NY, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Miron, Alexander F" sort="Miron, Alexander F" uniqKey="Miron A" first="Alexander F" last="Miron">Alexander F. Miron</name>
<affiliation><nlm:aff id="I133">Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goldgar, David" sort="Goldgar, David" uniqKey="Goldgar D" first="David" last="Goldgar">David Goldgar</name>
<affiliation><nlm:aff id="I134">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name>
<affiliation><nlm:aff id="I10">Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</nlm:aff>
</affiliation>
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<author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F" last="Easton">Douglas F. Easton</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
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<author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L" last="Andrulis">Irene L. Andrulis</name>
<affiliation><nlm:aff id="I135">Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada; Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Antoniou, Antonis C" sort="Antoniou, Antonis C" uniqKey="Antoniou A" first="Antonis C" last="Antoniou">Antonis C. Antoniou</name>
<affiliation><nlm:aff id="I3">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</nlm:aff>
</affiliation>
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</analytic>
<series><title level="j">Breast Cancer Research : BCR</title>
<idno type="ISSN">1465-5411</idno>
<idno type="eISSN">1465-542X</idno>
<imprint><date when="2011">2011</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Introduction</title>
<p>Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for <italic>BRCA1 </italic>
and/or <italic>BRCA2 </italic>
mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.</p>
</sec>
<sec><title>Methods</title>
<p>We used genotype data on up to 11,421 <italic>BRCA1 </italic>
and 7,080 <italic>BRCA2 </italic>
carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.</p>
</sec>
<sec><title>Results</title>
<p>The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers. Among <italic>BRCA1 </italic>
carriers, single nucleotide polymorphism (SNP) rs2981582 (<italic>FGFR2) </italic>
exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, <italic>P</italic>
-heterogeneity = 6.5 × 10<sup>-6</sup>
). In contrast, SNP rs2046210 at 6q25.1 near <italic>ESR1 </italic>
was primarily associated with ER-negative breast cancer risk for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers. In <italic>BRCA2 </italic>
carriers, SNPs in <italic>FGFR2, TOX3, LSP1, SLC4A7/NEK10</italic>
, 5p12, 2q35, and 1p11.<italic>2 </italic>
were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.</p>
</sec>
<sec><title>Conclusions</title>
<p>The associations of the 12 SNPs with risk for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.</p>
</sec>
</div>
</front>
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<article-id pub-id-type="doi">10.1186/bcr3052</article-id>
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<email>r.b.vanderluijt@umcutrecht.nl</email>
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<contrib contrib-type="author" id="A49"><name><surname>Os</surname>
<given-names>Theo van</given-names>
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</contrib>
<contrib contrib-type="author" id="A50"><name><surname>Rookus</surname>
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<email>m.rookus@nki.nl</email>
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<contrib contrib-type="author" id="A51"><name><surname>Frost</surname>
<given-names>Debra</given-names>
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<xref ref-type="aff" rid="I3">3</xref>
<email>debra.frost@srl.cam.ac.uk</email>
</contrib>
<contrib contrib-type="author" id="A52"><name><surname>Jones</surname>
<given-names>J Louise</given-names>
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<given-names>D Gareth</given-names>
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<email>Gareth.Evans@cmft.nhs.uk</email>
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<contrib contrib-type="author" id="A54"><name><surname>Lalloo</surname>
<given-names>Fiona</given-names>
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<email>Fiona.Lalloo@cmft.nhs.uk</email>
</contrib>
<contrib contrib-type="author" id="A55"><name><surname>Eeles</surname>
<given-names>Ros</given-names>
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<email>Rosalind.Eeles@icr.ac.uk</email>
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<contrib contrib-type="author" id="A56"><name><surname>Izatt</surname>
<given-names>Louise</given-names>
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<email>Julian.Adlard@leedsth.nhs.uk</email>
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<contrib contrib-type="author" id="A58"><name><surname>Davidson</surname>
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<email>Alan.Donaldson@UHBristol.nhs.uk</email>
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<contrib contrib-type="author" id="A61"><name><surname>Dorkins</surname>
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<email>h.dorkins@imperial.ac.uk</email>
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<email>helen.gregory2@nhs.net</email>
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<email>jacqueline.eason@nuh.nhs.uk</email>
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<email>Julian.Barwell@uhl-tr.nhs.uk</email>
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<contrib contrib-type="author" id="A66"><name><surname>Side</surname>
<given-names>Lucy E</given-names>
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<email>SideL@gosh.nhs.uk</email>
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<contrib contrib-type="author" id="A67"><name><surname>McCann</surname>
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<xref ref-type="aff" rid="I56">56</xref>
<email>emma.mccann@cd-tr.wales.nhs.uk</email>
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<email>alex.murray@wales.nhs.uk</email>
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<given-names>Rita K</given-names>
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<email>Rita.Schmutzler@uk-koeln.de</email>
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<given-names>Kerstin</given-names>
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<xref ref-type="aff" rid="I11">11</xref>
<email>Kerstin.Rhiem@uk-koeln.de</email>
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<contrib contrib-type="author" id="A73"><name><surname>Engel</surname>
<given-names>Christoph</given-names>
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<email>christoph.engel@imise.uni-leipzig.de</email>
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<contrib contrib-type="author" id="A74"><name><surname>Meindl</surname>
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<email>Alfons.Meindl@lrz.tu-muenchen.de</email>
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<contrib contrib-type="author" id="A75"><name><surname>Ruehl</surname>
<given-names>Ina</given-names>
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<email>Ina.Ruehl@med.uni-muenchen.de</email>
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<contrib contrib-type="author" id="A76"><name><surname>Arnold</surname>
<given-names>Norbert</given-names>
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<email>nkarnold@email.uni-kiel.de</email>
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<contrib contrib-type="author" id="A77"><name><surname>Niederacher</surname>
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<xref ref-type="aff" rid="I63">63</xref>
<email>niederac@uni-duesseldorf.de</email>
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<contrib contrib-type="author" id="A78"><name><surname>Sutter</surname>
<given-names>Christian</given-names>
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<email>C.Sutter@med.uni-heidelberg.de</email>
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<contrib contrib-type="author" id="A79"><name><surname>Deissler</surname>
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<email>helmut.deissler@uniklinik-ulm.de</email>
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<contrib contrib-type="author" id="A80"><name><surname>Gadzicki</surname>
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<email>Gadzicki.Dorothea@MH-Hannover.de</email>
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<contrib contrib-type="author" id="A81"><name><surname>Kast</surname>
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<email>Karin-Kast@uniklinikum-dresden.de</email>
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<contrib contrib-type="author" id="A82"><name><surname>Preisler-Adams</surname>
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<email>adamss@uni-muenster.de</email>
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<contrib contrib-type="author" id="A83"><name><surname>Varon-Mateeva</surname>
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<email>raymonda-varon-mateeva@charite.de</email>
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<email>schoenbuchner@biozentrum.uni-wuerzburg.de</email>
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<email>Britta.Fiebig@klinik.uni-regensburg.de</email>
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<email>heinw@medizin.uni-leibzig.de</email>
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<email>Heidrun.Gevensleben@icr.ac.uk</email>
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<contrib contrib-type="author" id="A89"><name><surname>Caux-Moncoutier</surname>
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<email>virginie.moncoutier@curie.net</email>
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<contrib contrib-type="author" id="A90"><name><surname>Fassy-Colcombet</surname>
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<email>marion.fassy-colcombet@curie.net</email>
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<contrib contrib-type="author" id="A91"><name><surname>Cornelis</surname>
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<email>fcornelis@chu-clermontferrand.fr</email>
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<contrib contrib-type="author" id="A92"><name><surname>Mazoyer</surname>
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<email>MAZOYER@lyon.fnclcc.fr</email>
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<email>LEONE@lyon.fnclcc.fr</email>
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<contrib contrib-type="author" id="A94"><name><surname>Boutry-Kryza</surname>
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<email>nadia.kryza@chu-lyon.fr</email>
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<contrib contrib-type="author" id="A95"><name><surname>Hardouin</surname>
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<email>A.HARDOUIN@baclesse.fr</email>
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<email>p.berthet@baclesse.fr</email>
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<given-names>Danièle</given-names>
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<email>dmuller@strasbourg.fnclcc.fr</email>
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<contrib contrib-type="author" id="A98"><name><surname>Fricker</surname>
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<email>jfricker@strasbourg.fnclcc.fr</email>
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<contrib contrib-type="author" id="A99"><name><surname>Mortemousque</surname>
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<email>mortemou@med.univ-tours.fr</email>
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<given-names>Pascal</given-names>
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<email>marine.lebrun@chu-st-etienne.fr</email>
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<contrib contrib-type="author" id="A103"><name><surname>Kientz</surname>
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<xref ref-type="aff" rid="I83">83</xref>
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<contrib contrib-type="author" id="A109"><name><surname>de la Hoya</surname>
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<xref ref-type="aff" rid="I8">8</xref>
<email>sakrr@mskcc.org</email>
</contrib>
<contrib contrib-type="author" id="A136"><name><surname>Gaudet</surname>
<given-names>Mia</given-names>
</name>
<xref ref-type="aff" rid="I104">104</xref>
<email>mia.gaudet@cancer.org</email>
</contrib>
<contrib contrib-type="author" id="A137"><name><surname>Bhatia</surname>
<given-names>Jasmine</given-names>
</name>
<xref ref-type="aff" rid="I8">8</xref>
<email>bhatiaj@mskcc.org</email>
</contrib>
<contrib contrib-type="author" id="A138"><name><surname>Kauff</surname>
<given-names>Noah</given-names>
</name>
<xref ref-type="aff" rid="I8">8</xref>
<email>kauffn@mskcc.org</email>
</contrib>
<contrib contrib-type="author" id="A139"><name><surname>Singer</surname>
<given-names>Christian F</given-names>
</name>
<xref ref-type="aff" rid="I105">105</xref>
<email>Christian.singer@meduniwien.ac.at</email>
</contrib>
<contrib contrib-type="author" id="A140"><name><surname>Tea</surname>
<given-names>Muy-Kheng</given-names>
</name>
<xref ref-type="aff" rid="I105">105</xref>
<email>muy-kheng.tea@meduniwien.ac.at</email>
</contrib>
<contrib contrib-type="author" id="A141"><name><surname>Gschwantler-Kaulich</surname>
<given-names>Daphne</given-names>
</name>
<xref ref-type="aff" rid="I105">105</xref>
<email>daphne.gschwantler-kaulich@meduniwien.ac.at</email>
</contrib>
<contrib contrib-type="author" id="A142"><name><surname>Fink-Retter</surname>
<given-names>Anneliese</given-names>
</name>
<xref ref-type="aff" rid="I105">105</xref>
<email>anneliese.fink-retter@meduniwien.ac.at</email>
</contrib>
<contrib contrib-type="author" id="A143"><name><surname>Mai</surname>
<given-names>Phuong L</given-names>
</name>
<xref ref-type="aff" rid="I106">106</xref>
<email>maip@mail.nih.gov</email>
</contrib>
<contrib contrib-type="author" id="A144"><name><surname>Greene</surname>
<given-names>Mark H</given-names>
</name>
<xref ref-type="aff" rid="I106">106</xref>
<email>greenem@mail.nih.gov</email>
</contrib>
<contrib contrib-type="author" id="A145"><name><surname>Imyanitov</surname>
<given-names>Evgeny</given-names>
</name>
<xref ref-type="aff" rid="I107">107</xref>
<email>evgeny@imyanitov.spb.ru</email>
</contrib>
<contrib contrib-type="author" id="A146"><name><surname>O'Malley</surname>
<given-names>Frances P</given-names>
</name>
<xref ref-type="aff" rid="I108">108</xref>
<email>OMalleyF@smh.ca</email>
</contrib>
<contrib contrib-type="author" id="A147"><name><surname>Ozcelik</surname>
<given-names>Hilmi</given-names>
</name>
<xref ref-type="aff" rid="I109">109</xref>
<email>ozcelik@lunenfeld.ca</email>
</contrib>
<contrib contrib-type="author" id="A148"><name><surname>Glendon</surname>
<given-names>Gordon</given-names>
</name>
<xref ref-type="aff" rid="I110">110</xref>
<email>gord.glendon@cancercare.on.ca</email>
</contrib>
<contrib contrib-type="author" id="A149"><name><surname>Toland</surname>
<given-names>Amanda E</given-names>
</name>
<xref ref-type="aff" rid="I111">111</xref>
<email>Amanda.Toland@osumc.edu</email>
</contrib>
<contrib contrib-type="author" id="A150"><name><surname>Gerdes</surname>
<given-names>Anne-Marie</given-names>
</name>
<xref ref-type="aff" rid="I112">112</xref>
<email>anne-marie.gerdes@rh.regionh.dk</email>
</contrib>
<contrib contrib-type="author" id="A151"><name><surname>Thomassen</surname>
<given-names>Mads</given-names>
</name>
<xref ref-type="aff" rid="I113">113</xref>
<email>mads.thomassen@ouh.regionsyddanmark.dk</email>
</contrib>
<contrib contrib-type="author" id="A152"><name><surname>Kruse</surname>
<given-names>Torben A</given-names>
</name>
<xref ref-type="aff" rid="I113">113</xref>
<email>torben.kruse@ouh.regionsyddanmark.dk</email>
</contrib>
<contrib contrib-type="author" id="A153"><name><surname>Jensen</surname>
<given-names>Uffe Birk</given-names>
</name>
<xref ref-type="aff" rid="I114">114</xref>
<email>uffejens@rm.dk</email>
</contrib>
<contrib contrib-type="author" id="A154"><name><surname>Skytte</surname>
<given-names>Anne-Bine</given-names>
</name>
<xref ref-type="aff" rid="I115">115</xref>
<email>anne-bine.skytte@slb.regionsyddanmark.dk</email>
</contrib>
<contrib contrib-type="author" id="A155"><name><surname>Caligo</surname>
<given-names>Maria A</given-names>
</name>
<xref ref-type="aff" rid="I116">116</xref>
<email>m.caligo@med.unipi.it</email>
</contrib>
<contrib contrib-type="author" id="A156"><name><surname>Soller</surname>
<given-names>Maria</given-names>
</name>
<xref ref-type="aff" rid="I117">117</xref>
<email>maria.soller@med.lu.se</email>
</contrib>
<contrib contrib-type="author" id="A157"><name><surname>Henriksson</surname>
<given-names>Karin</given-names>
</name>
<xref ref-type="aff" rid="I118">118</xref>
<email>Karin.O.Henriksson@skane.se</email>
</contrib>
<contrib contrib-type="author" id="A158"><name><surname>Wachenfeldt</surname>
<given-names>von Anna</given-names>
</name>
<xref ref-type="aff" rid="I119">119</xref>
<email>annavwachenfeldt@hotmail.com</email>
</contrib>
<contrib contrib-type="author" id="A159"><name><surname>Arver</surname>
<given-names>Brita</given-names>
</name>
<xref ref-type="aff" rid="I119">119</xref>
<email>brita.wasteson-arver@karolinska.se</email>
</contrib>
<contrib contrib-type="author" id="A160"><name><surname>Stenmark-Askmalm</surname>
<given-names>Marie</given-names>
</name>
<xref ref-type="aff" rid="I120">120</xref>
<email>marie.stenmark.askmalm@lio.se</email>
</contrib>
<contrib contrib-type="author" id="A161"><name><surname>Karlsson</surname>
<given-names>Per</given-names>
</name>
<xref ref-type="aff" rid="I121">121</xref>
<email>per.karlsson@oncology.gu.se</email>
</contrib>
<contrib contrib-type="author" id="A162"><name><surname>Ding</surname>
<given-names>Yuan Chun</given-names>
</name>
<xref ref-type="aff" rid="I122">122</xref>
<email>ycding@coh.org</email>
</contrib>
<contrib contrib-type="author" id="A163"><name><surname>Neuhausen</surname>
<given-names>Susan L</given-names>
</name>
<xref ref-type="aff" rid="I122">122</xref>
<email>sneuhausen@coh.org</email>
</contrib>
<contrib contrib-type="author" id="A164"><name><surname>Beattie</surname>
<given-names>Mary</given-names>
</name>
<xref ref-type="aff" rid="I123">123</xref>
<email>mary.beattie@ucsfmedctr.org</email>
</contrib>
<contrib contrib-type="author" id="A165"><name><surname>Pharoah</surname>
<given-names>Paul DP</given-names>
</name>
<xref ref-type="aff" rid="I124">124</xref>
<email>paul.pharoah@srl.cam.ac.uk</email>
</contrib>
<contrib contrib-type="author" id="A166"><name><surname>Moysich</surname>
<given-names>Kirsten B</given-names>
</name>
<xref ref-type="aff" rid="I125">125</xref>
<email>Kirsten.moysich@roswellpark.org</email>
</contrib>
<contrib contrib-type="author" id="A167"><name><surname>Nathanson</surname>
<given-names>Katherine L</given-names>
</name>
<xref ref-type="aff" rid="I4">4</xref>
<email>knathans@exchange.upenn.edu</email>
</contrib>
<contrib contrib-type="author" id="A168"><name><surname>Karlan</surname>
<given-names>Beth Y</given-names>
</name>
<xref ref-type="aff" rid="I126">126</xref>
<email>Beth.Karlan@cshs.org</email>
</contrib>
<contrib contrib-type="author" id="A169"><name><surname>Gross</surname>
<given-names>Jenny</given-names>
</name>
<xref ref-type="aff" rid="I126">126</xref>
<email>Jenny.Gross@cshs.org</email>
</contrib>
<contrib contrib-type="author" id="A170"><name><surname>John</surname>
<given-names>Esther M</given-names>
</name>
<xref ref-type="aff" rid="I127">127</xref>
<email>ejohn@nccc.org</email>
</contrib>
<contrib contrib-type="author" id="A171"><name><surname>Daly</surname>
<given-names>Mary B</given-names>
</name>
<xref ref-type="aff" rid="I128">128</xref>
<email>mary.daly@fccc.edu</email>
</contrib>
<contrib contrib-type="author" id="A172"><name><surname>Buys</surname>
<given-names>Saundra M</given-names>
</name>
<xref ref-type="aff" rid="I129">129</xref>
<email>saundra.buys@hci.utah.edu</email>
</contrib>
<contrib contrib-type="author" id="A173"><name><surname>Southey</surname>
<given-names>Melissa C</given-names>
</name>
<xref ref-type="aff" rid="I130">130</xref>
<email>msouthey@unimelb.edu.au</email>
</contrib>
<contrib contrib-type="author" id="A174"><name><surname>Hopper</surname>
<given-names>John L</given-names>
</name>
<xref ref-type="aff" rid="I131">131</xref>
<email>j.hopper@unimelb.edu.au</email>
</contrib>
<contrib contrib-type="author" id="A175"><name><surname>Terry</surname>
<given-names>Mary Beth</given-names>
</name>
<xref ref-type="aff" rid="I132">132</xref>
<email>mt146@columbia.edu</email>
</contrib>
<contrib contrib-type="author" id="A176"><name><surname>Chung</surname>
<given-names>Wendy</given-names>
</name>
<xref ref-type="aff" rid="I132">132</xref>
<email>wkc15@columbia.edu</email>
</contrib>
<contrib contrib-type="author" id="A177"><name><surname>Miron</surname>
<given-names>Alexander F</given-names>
</name>
<xref ref-type="aff" rid="I133">133</xref>
<email>alexander_miron@dfci.harvard.edu</email>
</contrib>
<contrib contrib-type="author" id="A178"><name><surname>Goldgar</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="I134">134</xref>
<email>david.goldgar@hsc.utah.edu</email>
</contrib>
<contrib contrib-type="author" id="A179"><name><surname>Chenevix-Trench</surname>
<given-names>Georgia</given-names>
</name>
<xref ref-type="aff" rid="I10">10</xref>
<email>Georgia.Trench@qimr.edu.au</email>
</contrib>
<contrib contrib-type="author" id="A180"><name><surname>Easton</surname>
<given-names>Douglas F</given-names>
</name>
<xref ref-type="aff" rid="I3">3</xref>
<email>douglas@srl.cam.ac.uk</email>
</contrib>
<contrib contrib-type="author" id="A181"><name><surname>Andrulis</surname>
<given-names>Irene L</given-names>
</name>
<xref ref-type="aff" rid="I135">135</xref>
<email>andrulis@lunenfeld.ca</email>
</contrib>
<contrib contrib-type="author" corresp="yes" id="A182"><name><surname>Antoniou</surname>
<given-names>Antonis C</given-names>
</name>
<xref ref-type="aff" rid="I3">3</xref>
<email>antonis@srl.cam.ac.uk</email>
</contrib>
<on-behalf-of>Breast Cancer Family Registry daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>EMBRACE daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>GEMO Study Collaborators daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>HEBON daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>kConFab Investigators daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>Ontario Cancer Genetics Network daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>SWE-BRCA daniel@srl.cam.ac.uk</on-behalf-of>
<on-behalf-of>CIMBA</on-behalf-of>
</contrib-group>
<aff id="I1"><label>1</label>
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada</aff>
<aff id="I2"><label>2</label>
Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA</aff>
<aff id="I3"><label>3</label>
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK</aff>
<aff id="I4"><label>4</label>
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA</aff>
<aff id="I5"><label>5</label>
Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK</aff>
<aff id="I6"><label>6</label>
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland</aff>
<aff id="I7"><label>7</label>
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N Soto Street, Los Angeles, CA 90089-9237, USA</aff>
<aff id="I8"><label>8</label>
Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA</aff>
<aff id="I9"><label>9</label>
National Cancer Institute, Division of Cancer Epidemiology and Genetics, Hormonal and Reproductive Epidemiology Branch, 6120 Executive Blvd., Rockville, MD 20852, USA</aff>
<aff id="I10"><label>10</label>
Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia</aff>
<aff id="I11"><label>11</label>
Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany</aff>
<aff id="I12"><label>12</label>
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France</aff>
<aff id="I13"><label>13</label>
INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France</aff>
<aff id="I14"><label>14</label>
Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, Santariskiu st 2, LT-08661 Vilnius and State Research Institute Innovative Medicine Center, Zygimantu st. 9, LT-01102 Vilnius, Lithuania</aff>
<aff id="I15"><label>15</label>
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</aff>
<aff id="I16"><label>16</label>
Department of Oncology, Rigshospitalet Bldg. 4262, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark</aff>
<aff id="I17"><label>17</label>
Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</aff>
<aff id="I18"><label>18</label>
Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), C/Sanz y Forés, N° 3, Valladolid, 47003, Spain</aff>
<aff id="I19"><label>19</label>
Instituto de investigación sanitaria de Aragón (IIS), Hospital clinico Universitario "Lozano Blesa", San Juan Bosco 15, Zaragoza, 50009, Spain</aff>
<aff id="I20"><label>20</label>
Molecular Diagnostics Laboratory, IRRP, National Center for Scientific Research Demokritos, Patriarchou Gregoriou E' & Neapoleos Str, Ag. Paraskevi 15310, Athens, Greece</aff>
<aff id="I21"><label>21</label>
Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)</aff>
<aff id="I22"><label>22</label>
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, 20133 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, 20139 Milan, Italy</aff>
<aff id="I23"><label>23</label>
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy</aff>
<aff id="I24"><label>24</label>
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, via Ripamonti 435, Milan, 20141, Italy</aff>
<aff id="I25"><label>25</label>
Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy</aff>
<aff id="I26"><label>26</label>
Department of Genetics, Biology and BiochemIstry, University of Turin, Turin, Italy</aff>
<aff id="I27"><label>27</label>
Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Firenze, Italy</aff>
<aff id="I28"><label>28</label>
Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy</aff>
<aff id="I29"><label>29</label>
Division of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy</aff>
<aff id="I30"><label>30</label>
Department of Experimental Oncology, Istituto Europeo di Oncologia. Milan, Italy; Consortium for Genomics Technology (Cogentech), Milan, Italy</aff>
<aff id="I31"><label>31</label>
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany</aff>
<aff id="I32"><label>32</label>
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</aff>
<aff id="I33"><label>33</label>
Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands</aff>
<aff id="I34"><label>34</label>
Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</aff>
<aff id="I35"><label>35</label>
Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands</aff>
<aff id="I36"><label>36</label>
Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands</aff>
<aff id="I37"><label>37</label>
Department of Human Genetics 836, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands</aff>
<aff id="I38"><label>38</label>
Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands</aff>
<aff id="I39"><label>39</label>
Department of Surgical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands</aff>
<aff id="I40"><label>40</label>
Department of Medical Genetics, University Medical Center Utrecht, The Netherlands</aff>
<aff id="I41"><label>41</label>
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands</aff>
<aff id="I42"><label>42</label>
Barts Cancer Institute, Queen Mary University of London, Centre for Tumour Biology, Charterhouse Square, London, UK</aff>
<aff id="I43"><label>43</label>
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK</aff>
<aff id="I44"><label>44</label>
Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK</aff>
<aff id="I45"><label>45</label>
Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK</aff>
<aff id="I46"><label>46</label>
Yorkshire Regional Genetics Service, Leeds, UK</aff>
<aff id="I47"><label>47</label>
Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK</aff>
<aff id="I48"><label>48</label>
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK</aff>
<aff id="I49"><label>49</label>
Clinical Genetics Department, St Michael's Hospital, Bristol, UK</aff>
<aff id="I50"><label>50</label>
North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK</aff>
<aff id="I51"><label>51</label>
North of Scotland Regional Genetics Service, NHS Grampian and University of Aberdeen, Foresterhill, Aberdeen, UK</aff>
<aff id="I52"><label>52</label>
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, UK</aff>
<aff id="I53"><label>53</label>
Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK</aff>
<aff id="I54"><label>54</label>
Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, UK</aff>
<aff id="I55"><label>55</label>
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK</aff>
<aff id="I56"><label>56</label>
All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK</aff>
<aff id="I57"><label>57</label>
All Wales Medical Genetics Services, Singleton Hospital, Swansea, UK</aff>
<aff id="I58"><label>58</label>
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA</aff>
<aff id="I59"><label>59</label>
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany</aff>
<aff id="I60"><label>60</label>
Department of Gynaecology and Obstetrics, Division of Tumour Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany</aff>
<aff id="I61"><label>61</label>
Department of Gynaecology and Obstetrics, Ludwig-Maximillians University, Munich, Germany</aff>
<aff id="I62"><label>62</label>
Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Christian-Albrechts University, Kiel, Germany</aff>
<aff id="I63"><label>63</label>
Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany</aff>
<aff id="I64"><label>64</label>
Institute of Human Genetics, Department of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany</aff>
<aff id="I65"><label>65</label>
Department of Gynaecology and Obstetrics, University Hospital, Ulm, Germany</aff>
<aff id="I66"><label>66</label>
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany</aff>
<aff id="I67"><label>67</label>
Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University, Dresden, Germany</aff>
<aff id="I68"><label>68</label>
Institute of Human Genetics, University of Münster, Münster, Germany</aff>
<aff id="I69"><label>69</label>
Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany</aff>
<aff id="I70"><label>70</label>
Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Germany</aff>
<aff id="I71"><label>71</label>
Institute of Human Genetics, University Regensburg, Germany</aff>
<aff id="I72"><label>72</label>
Institute of Human Genetics, University Leipzig, Germany</aff>
<aff id="I73"><label>73</label>
Institute of Human Genetics, University Hospital, Frankfurt a.M., Germany</aff>
<aff id="I74"><label>74</label>
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, UK</aff>
<aff id="I75"><label>75</label>
Service de Génétique Oncologique, Institut Curie, Paris, France</aff>
<aff id="I76"><label>76</label>
Genetic Unit, Avicenne Hospital, Assitance Publique-Hôpitaux de Paris, Paris, France; Sud-Francilien Hospital, Evry-Corbeil, France; University Hospital, Clermont-Ferrand, France</aff>
<aff id="I77"><label>77</label>
Centre François Baclesse, Caen, France</aff>
<aff id="I78"><label>78</label>
Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France</aff>
<aff id="I79"><label>79</label>
Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France</aff>
<aff id="I80"><label>80</label>
Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France</aff>
<aff id="I81"><label>81</label>
Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France</aff>
<aff id="I82"><label>82</label>
Cancer Genetics Unit, INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France</aff>
<aff id="I83"><label>83</label>
Unité INSERM U830, Institut Curie, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France</aff>
<aff id="I84"><label>84</label>
Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA</aff>
<aff id="I85"><label>85</label>
Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain</aff>
<aff id="I86"><label>86</label>
Department of Clinical Genetics, Helsinki University Central Hospital, Meilahdentie 2, 00290 Helsinki, Finland</aff>
<aff id="I87"><label>87</label>
Hereditary Cancer Program, Institut Català d'Oncologia, Hospital Duran i Reynals - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain</aff>
<aff id="I88"><label>88</label>
Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland, Faculty of Medicine, University of Iceland, Reykjavik, Iceland</aff>
<aff id="I89"><label>89</label>
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada</aff>
<aff id="I90"><label>90</label>
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada; Canada Research Chair in Oncogenetics, Department of Molecular Medicine, Faculty of Medicine, Laval University, QC, Canada</aff>
<aff id="I91"><label>91</label>
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</aff>
<aff id="I92"><label>92</label>
Department of Oncology and Surgical Sciences, University of Padua and Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy</aff>
<aff id="I93"><label>93</label>
Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia</aff>
<aff id="I94"><label>94</label>
Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia</aff>
<aff id="I95"><label>95</label>
Abramson Cancer Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA</aff>
<aff id="I96"><label>96</label>
University of Chicago, Chicago, IL, USA</aff>
<aff id="I97"><label>97</label>
City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA</aff>
<aff id="I98"><label>98</label>
Departments of Medicine, and Preventive Medicine and Public Health, Creighton University, Omaha, NE, USA</aff>
<aff id="I99"><label>99</label>
Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, CA, USA</aff>
<aff id="I100"><label>100</label>
Department of Internal Medicine and Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX; USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA</aff>
<aff id="I101"><label>101</label>
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA</aff>
<aff id="I102"><label>102</label>
Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA</aff>
<aff id="I103"><label>103</label>
University of Delaware, Newark, DE, USA</aff>
<aff id="I104"><label>104</label>
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA</aff>
<aff id="I105"><label>105</label>
Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria</aff>
<aff id="I106"><label>106</label>
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA</aff>
<aff id="I107"><label>107</label>
Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia</aff>
<aff id="I108"><label>108</label>
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada</aff>
<aff id="I109"><label>109</label>
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada</aff>
<aff id="I110"><label>110</label>
Cancer Care Ontario, ON, Canada</aff>
<aff id="I111"><label>111</label>
Departments of Molecular Virology, Immunology and Medical Genetics and Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA</aff>
<aff id="I112"><label>112</label>
Clinical Genetics, Rigshospital, Copenhagen University, Copenhagen, Denmark</aff>
<aff id="I113"><label>113</label>
Clinical Genetics, Odense University Hospital, Odense, Denmark</aff>
<aff id="I114"><label>114</label>
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark</aff>
<aff id="I115"><label>115</label>
Clinical Genetics, Vejle Hospital, Denmark</aff>
<aff id="I116"><label>116</label>
Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy</aff>
<aff id="I117"><label>117</label>
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden</aff>
<aff id="I118"><label>118</label>
Oncological Centre, Lund University Hospital, Lund, Sweden</aff>
<aff id="I119"><label>119</label>
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden</aff>
<aff id="I120"><label>120</label>
Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden</aff>
<aff id="I121"><label>121</label>
Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden</aff>
<aff id="I122"><label>122</label>
Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA, USA</aff>
<aff id="I123"><label>123</label>
UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA</aff>
<aff id="I124"><label>124</label>
Department of Oncology, University of Cambridge, Cambridge, UK</aff>
<aff id="I125"><label>125</label>
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA</aff>
<aff id="I126"><label>126</label>
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA</aff>
<aff id="I127"><label>127</label>
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA</aff>
<aff id="I128"><label>128</label>
Fox Chase Cancer Center, Philadelphia, PA, USA</aff>
<aff id="I129"><label>129</label>
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA</aff>
<aff id="I130"><label>130</label>
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, VIC, Australia</aff>
<aff id="I131"><label>131</label>
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, VIC, Australia</aff>
<aff id="I132"><label>132</label>
Department of Epidemiology, Columbia University, New York, NY, USA</aff>
<aff id="I133"><label>133</label>
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA</aff>
<aff id="I134"><label>134</label>
Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA</aff>
<aff id="I135"><label>135</label>
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada; Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada</aff>
<aff id="I136"><label>136</label>
Breast Cancer Family Registry</aff>
<aff id="I137"><label>137</label>
Cancer Genetics Network "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer</aff>
<aff id="I138"><label>138</label>
Netherlands Cancer Institute, Amsterdam, The Netherlands</aff>
<aff id="I139"><label>139</label>
Ontario Cancer Genetics Network, Cancer Care Ontario, 620 University Avenue, Toronto, ON M5G 2L7, Canada</aff>
<aff id="I140"><label>140</label>
Karolinska Institute, Stockholm, Sweden</aff>
<pub-date pub-type="ppub"><year>2011</year>
</pub-date>
<pub-date pub-type="epub"><day>2</day>
<month>11</month>
<year>2011</year>
</pub-date>
<volume>13</volume>
<issue>6</issue>
<fpage>R110</fpage>
<lpage>R110</lpage>
<history><date date-type="received"><day>27</day>
<month>4</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>2</day>
<month>11</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>Copyright ©2011 Mulligan et al.; licensee BioMed Central Ltd.</copyright-statement>
<copyright-year>2011</copyright-year>
<copyright-holder>Mulligan et al.; licensee BioMed Central Ltd.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri xlink:href="http://breast-cancer-research.com/content/13/6/R110"></self-uri>
<abstract><sec><title>Introduction</title>
<p>Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for <italic>BRCA1 </italic>
and/or <italic>BRCA2 </italic>
mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.</p>
</sec>
<sec><title>Methods</title>
<p>We used genotype data on up to 11,421 <italic>BRCA1 </italic>
and 7,080 <italic>BRCA2 </italic>
carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.</p>
</sec>
<sec><title>Results</title>
<p>The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers. Among <italic>BRCA1 </italic>
carriers, single nucleotide polymorphism (SNP) rs2981582 (<italic>FGFR2) </italic>
exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, <italic>P</italic>
-heterogeneity = 6.5 × 10<sup>-6</sup>
). In contrast, SNP rs2046210 at 6q25.1 near <italic>ESR1 </italic>
was primarily associated with ER-negative breast cancer risk for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers. In <italic>BRCA2 </italic>
carriers, SNPs in <italic>FGFR2, TOX3, LSP1, SLC4A7/NEK10</italic>
, 5p12, 2q35, and 1p11.<italic>2 </italic>
were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.</p>
</sec>
<sec><title>Conclusions</title>
<p>The associations of the 12 SNPs with risk for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.</p>
</sec>
</abstract>
</article-meta>
</front>
<body><sec><title>Introduction</title>
<p>Germline mutations in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
confer high risks of breast, ovarian and other cancers [<xref ref-type="bibr" rid="B1">1</xref>
-<xref ref-type="bibr" rid="B3">3</xref>
] and account for 15 to 20% of the excess familial risk of breast cancer among first degree relatives [<xref ref-type="bibr" rid="B4">4</xref>
,<xref ref-type="bibr" rid="B5">5</xref>
]. Breast cancer risks for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers have been estimated to range between 40 and 87% by age 70 [<xref ref-type="bibr" rid="B6">6</xref>
-<xref ref-type="bibr" rid="B12">12</xref>
] with population-based estimates tending to be lower than estimates based on families with multiple affected individuals [<xref ref-type="bibr" rid="B6">6</xref>
,<xref ref-type="bibr" rid="B8">8</xref>
]. Moreover, breast cancer risks for mutation carriers were found to vary according to the age at diagnosis and the type of cancer of the index patient involved in the family ascertainment [<xref ref-type="bibr" rid="B6">6</xref>
,<xref ref-type="bibr" rid="B7">7</xref>
,<xref ref-type="bibr" rid="B11">11</xref>
]. Such evidence suggests that genetic or other risk factors that cluster in families modify the cancer risks conferred by <italic>BRCA</italic>
1 and <italic>BRCA2 </italic>
mutations.</p>
<p>A substantial body of work indicates that tumours arising in patients with germline <italic>BRCA1 </italic>
mutations are morphologically and genetically distinct from those arising in carriers of <italic>BRCA2 </italic>
mutations and from tumours in patients lacking mutations. In gene expression studies, <italic>BRCA1</italic>
-associated tumours are often classified as basal subtype tumours [<xref ref-type="bibr" rid="B13">13</xref>
,<xref ref-type="bibr" rid="B14">14</xref>
]. This is reflected in their higher grade, and morphologic features including lymphocytic infiltrate, pushing margins and syncytial growth. Being basal-like they express several markers that are normally expressed in the basal/myoepithelial cells of the breast, including stratified epithelial cytokeratins 5/6, 14 and 17. <italic>BRCA1</italic>
-associated tumours are more likely to be estrogen receptor (ER), progesterone receptor (PR) and HER2 negative and to harbor mutations in the <italic>TP53 </italic>
gene than age-matched sporadic breast cancers [<xref ref-type="bibr" rid="B15">15</xref>
,<xref ref-type="bibr" rid="B16">16</xref>
]. <italic>BRCA2</italic>
-associated tumours are also predominantly high-grade invasive ductal carcinomas of no special type but they often demonstrate a luminal phenotype despite their high histologic grade [<xref ref-type="bibr" rid="B13">13</xref>
,<xref ref-type="bibr" rid="B17">17</xref>
]. Adjusting for grade, <italic>BRCA2</italic>
-associated tumours are more often ER-positive and are less likely, compared with controls, to express the basal cytokeratin CK5 or to overexpress HER2/neu protein [<xref ref-type="bibr" rid="B17">17</xref>
].</p>
<p>Establishing the estrogen receptor status of a breast cancer (positive or negative) reflects a major subdivision in breast cancer type (at least five major sub-types are recognized) and it is becoming clear that the risk factors associated with breast cancer, both genetic and epidemiological, differ according to sub-type. Genome-wide association studies (GWAS) in breast cancer have identified several common alleles (single nucleotide polymorphisms (SNPs)) associated with an increased risk of breast cancer in the general population [<xref ref-type="bibr" rid="B18">18</xref>
-<xref ref-type="bibr" rid="B25">25</xref>
]. Many of these SNPs are associated with risk for ER-positive breast cancer, fewer have so far been associated with ER-negative breast cancer risk [<xref ref-type="bibr" rid="B26">26</xref>
,<xref ref-type="bibr" rid="B27">27</xref>
].</p>
<p>Known risk breast cancer susceptibility alleles have been genotyped in a large series of female <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers assembled by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) to evaluate their associations with risk of breast cancer for mutation carriers. Of the 12 SNPs (rs2981582 in <italic>FGFR2</italic>
, rs3803662 in <italic>TOX3/TNRC9</italic>
, rs889312 in <italic>MAP3K1</italic>
, rs13281615 at 8q24, rs381798 in <italic>LSP1</italic>
, rs13387042 at 2q35, rs4973768 in <italic>SLC4A7/NEK10</italic>
, rs10941679 at 5p12, rs6504950 in <italic>STXBP4/COX11</italic>
, rs999737/rs10483813 in <italic>RAD51L1</italic>
, rs2046210 at 6q25.1 and rs11249433 at 1p11.2) investigated so far, eight were associated with breast cancer risk for <italic>BRCA2 </italic>
carriers (all but SNPs at 8q24, <italic>RAD51L1</italic>
, 6q25.1 and <italic>STXBP4/COX11</italic>
), whereas only three SNPs (6q25.1, <italic>TOX3/TNRC9 </italic>
and 2q35) were associated with risk for <italic>BRCA1 </italic>
mutation carriers [<xref ref-type="bibr" rid="B28">28</xref>
-<xref ref-type="bibr" rid="B31">31</xref>
]. Work from the Breast Cancer Association Consortium and subsequent studies have demonstrated differences in the associations between these susceptibility loci and tumour characteristics in the general population [<xref ref-type="bibr" rid="B27">27</xref>
,<xref ref-type="bibr" rid="B32">32</xref>
]. These results suggest that the observed differences in the associations between <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers may reflect differences in the distribution of tumour characteristics in mutation carriers. It is currently unclear whether these polymorphisms are associated with different tumour characteristics within <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers.</p>
<p>As an adjunct to predictive testing for a high risk <italic>BRCA1 </italic>
or <italic>BRCA2 </italic>
gene mutation, more individualized risk estimates that take into account additional genetic and environmental modifiers will require a more detailed understanding of how these various risk factors interact. Understanding whether common genetic variants modify the risks of developing ER-positive or ER-negative breast cancer in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers could potentially influence the clinical management of these individuals. For example, knowing that a <italic>BRCA1 </italic>
mutation carrier is more likely to develop ER-positive breast cancer (than most <italic>BRCA1 </italic>
mutation carriers), may influence the choice of management strategies, such as chemoprevention. In this study, we used data from the CIMBA consortium to evaluate the associations between the 12 common breast cancer susceptibility alleles and risk for breast cancer defined by ER and PR status.</p>
</sec>
<sec sec-type="materials|methods"><title>Materials and methods</title>
<sec><title>Subjects</title>
<p>Subjects were <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers recruited by 36 study centres in Europe, North America and Australia (Table <xref ref-type="table" rid="T1">1</xref>
). All carriers participated in clinical or research studies at the host institutions, which have been approved by local ethics committees (list provided in Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>
, Table S1). Each committee granted approval for access and use of the medical records for the present analyses.</p>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Number of mutation carriers by country grouping affection status and tumour marker characteristics</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left">Country Group</th>
<th align="center">BRCA1</th>
<th align="center">BRCA2</th>
<th align="center">Unaffected</th>
<th align="center">Breast Cancer</th>
<th align="center">ER-</th>
<th align="center">ER+</th>
<th align="center">PR-</th>
<th align="center">PR+</th>
</tr>
</thead>
<tbody><tr><td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="left">Austria<sup>1</sup>
</td>
<td align="center">465</td>
<td align="center">179</td>
<td align="center">318</td>
<td align="center">326</td>
<td align="center">76</td>
<td align="center">51</td>
<td align="center">76</td>
<td align="center">44</td>
</tr>
<tr><td align="left">Australia<sup>2</sup>
</td>
<td align="center">660</td>
<td align="center">552</td>
<td align="center">541</td>
<td align="center">671</td>
<td align="center">235</td>
<td align="center">200</td>
<td align="center">297</td>
<td align="center">121</td>
</tr>
<tr><td align="left">Canada<sup>3</sup>
</td>
<td align="center">443</td>
<td align="center">358</td>
<td align="center">386</td>
<td align="center">415</td>
<td align="center">107</td>
<td align="center">70</td>
<td align="center">89</td>
<td align="center">68</td>
</tr>
<tr><td align="left">Denmark<sup>4</sup>
</td>
<td align="center">507</td>
<td align="center">319</td>
<td align="center">463</td>
<td align="center">363</td>
<td align="center">98</td>
<td align="center">93</td>
<td align="center">79</td>
<td align="center">45</td>
</tr>
<tr><td align="left">France-Belgium-Spain<sup>5</sup>
</td>
<td align="center">1,673</td>
<td align="center">1,256</td>
<td align="center">1,217</td>
<td align="center">1,712</td>
<td align="center">140</td>
<td align="center">165</td>
<td align="center">1,661</td>
<td align="center">127</td>
</tr>
<tr><td align="left">Finland<sup>6</sup>
</td>
<td align="center">103</td>
<td align="center">105</td>
<td align="center">91</td>
<td align="center">117</td>
<td align="center">59</td>
<td align="center">54</td>
<td align="center">74</td>
<td align="center">39</td>
</tr>
<tr><td align="left">Germany<sup>7</sup>
</td>
<td align="center">1,231</td>
<td align="center">589</td>
<td align="center">648</td>
<td align="center">1,172</td>
<td align="center">443</td>
<td align="center">336</td>
<td align="center">457</td>
<td align="center">311</td>
</tr>
<tr><td align="left">Iceland<sup>8</sup>
</td>
<td align="center">0</td>
<td align="center">135</td>
<td align="center">24</td>
<td align="center">111</td>
<td align="center">21</td>
<td align="center">57</td>
<td align="center">18</td>
<td align="center">57</td>
</tr>
<tr><td align="left">Italy<sup>9</sup>
</td>
<td align="center">994</td>
<td align="center">666</td>
<td align="center">686</td>
<td align="center">974</td>
<td align="center">203</td>
<td align="center">251</td>
<td align="center">231</td>
<td align="center">216</td>
</tr>
<tr><td align="left">Latvia-Lithuania-Russia<sup>10</sup>
</td>
<td align="center">190</td>
<td align="center">0</td>
<td align="center">79</td>
<td align="center">111</td>
<td align="center">21</td>
<td align="center">6</td>
<td align="center">18</td>
<td align="center">7</td>
</tr>
<tr><td align="left">Sweden<sup>11</sup>
</td>
<td align="center">537</td>
<td align="center">177</td>
<td align="center">396</td>
<td align="center">318</td>
<td align="center">86</td>
<td align="center">54</td>
<td align="center">89</td>
<td align="center">50</td>
</tr>
<tr><td align="left">Netherlands<sup>12</sup>
</td>
<td align="center">804</td>
<td align="center">319</td>
<td align="center">611</td>
<td align="center">512</td>
<td align="center">72</td>
<td align="center">41</td>
<td align="center">69</td>
<td align="center">29</td>
</tr>
<tr><td align="left">UK-Eire<sup>13</sup>
</td>
<td align="center">1,107</td>
<td align="center">866</td>
<td align="center">1,008</td>
<td align="center">965</td>
<td align="center">268</td>
<td align="center">239</td>
<td align="center">175</td>
<td align="center">104</td>
</tr>
<tr><td align="left">USA<sup>14</sup>
</td>
<td align="center">2,707</td>
<td align="center">1559</td>
<td align="center">2,118</td>
<td align="center">2048</td>
<td align="center">482</td>
<td align="center">366</td>
<td align="center">512</td>
<td align="center">297</td>
</tr>
<tr><td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="left">Total</td>
<td align="center">11,421</td>
<td align="center">7,080</td>
<td align="center">8,686</td>
<td align="center">9,815</td>
<td align="center">2,311</td>
<td align="center">1,983</td>
<td align="center">2,345</td>
<td align="center">1,515</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Studies in country groups:1:MUV; 2:BCFR/KCONFAB; 3:OCGN/BCFR/INHERIT; 4:CBCS/OUH; 5: GEMO/CNIO/HCSC/ICO/MOD-SQUAD; 6:HEBCS; 7:GC-HBOC/DKFZ; 8:ILUH; 9:CONSIT-TEAM/IOVHBOCS/PBCS; 10: NNPIO/BFBOCC; 11: SWE-BRCA; 12: HEBON; 13:EMBRACE/UKGRFOCR; 14:FCCC/GEMO/GEORGETOWN/MAGIC/MAYO/MSKCC/NCI/OSU-CCG/UCI/UCSF/UKGRFOCR/UPENN/WCRI</p>
</table-wrap-foot>
</table-wrap>
<p>The large majority of carriers were recruited through cancer genetics clinics offering genetic testing, and enrolled into national or regional studies. Eligibility to participate in CIMBA is restricted to female carriers of pathogenic <italic>BRCA1 </italic>
or <italic>BRCA2 </italic>
mutations who were 18 years old or older at recruitment. Information collected included the year of birth; mutation description, including nucleotide position and base change; age at last follow-up; ages at breast and ovarian cancer diagnoses; and age or date at bilateral prophylactic mastectomy. Information was also available on the country of residence. Related individuals were identified through a unique family identifier. Women were included in the analysis if they carried mutations that were pathogenic according to generally recognized criteria. Only studies that provided tumour pathology information and had genotype information were included in the analysis. However, to maximise the available information, genotyped mutation carriers within those studies missing information on tumour characteristics were included in the analysis and their disease subtype was assumed to be missing at random (see statistical methods for details). Further details about the CIMBA initiative can be found elsewhere [<xref ref-type="bibr" rid="B33">33</xref>
].</p>
</sec>
<sec><title>Tumour pathology data collection</title>
<p>Tumour pathology data were amalgamated from a range of sources, specifically patient pathology reports, medical records, pathology review data, tumour registry records and results from tissue microarrays. Estrogen and progesterone receptor status was provided as negative or positive, with supplementary immunohistochemistry scoring data and methodology provided when available. Based on definitions supplied, most centres employed a cut off of ≥10% of tumour cells stained positive to define receptor positivity. To ensure consistency across studies, when information on the proportion of cells stained was available, we used the same cut-off to define ER and PR positive tumours. For a small number of cases where composite scoring methods based on the proportion and intensity of staining were available (Allred score, Remmele score and H-score), widely-accepted cut-offs were used (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>
, Table S2). Consistency checks were performed to validate receptor data against supplementary scoring information if provided.</p>
</sec>
<sec><title>Genotyping</title>
<p>This analysis included genotype data on 12 SNPs that had been previously assessed for their associations with the overall risk of breast cancer for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers in CIMBA. Genotyping was performed using either the iPLEX or Taqman platforms and has been described in detail in the previous reports [<xref ref-type="bibr" rid="B28">28</xref>
-<xref ref-type="bibr" rid="B31">31</xref>
]. To ensure genotyping consistency, all genotyping centres were required to adhere to the CIMBA genotyping quality control criteria which are described in detail online [<xref ref-type="bibr" rid="B34">34</xref>
]. The 12 SNPs genotyped were rs2981582 in <italic>FGFR2</italic>
, rs3803662 in <italic>TOX3/TNRC9</italic>
, rs889312 in <italic>MAP3K1</italic>
, rs3817198 in <italic>LSP1</italic>
, rs13387042 at 2q35, rs13281615 at 8q24, rs4973768 near <italic>SLC4A7/NEK10</italic>
, rs6504950 in the <italic>STXBP4/COX11 </italic>
region, rs2046210 near <italic>ESR1 </italic>
at 6q25.1 and rs11249433 at 1p11.2. A Taqman assay could not be adequately designed for SNP rs999737 in the <italic>RAD51L1 </italic>
region and studies using this platform genotyped the surrogate SNP rs10483813 (pair-wise r<sup>2 </sup>
= 1 with rs999737 based on HapMap CEU data). Data for these two SNPs were combined and treated as a single locus in the analysis of associations.</p>
</sec>
<sec><title>Statistical analysis</title>
<p>The aim of this study was to evaluate the associations between each genotype and breast cancer subtypes defined by tumour characteristics in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers separately. The phenotype of each individual was defined by the age at diagnosis of breast cancer and its subtype or by age at last follow-up. Individuals were censored at the age of the first breast cancer diagnosis, ovarian cancer diagnosis, or bilateral prophylactic mastectomy or the age at last observation. Mutation carriers censored at ovarian cancer diagnosis were considered unaffected.</p>
<p>The analysis of risk modifiers in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers is complicated by the fact that mutation carriers are not randomly sampled with respect to their disease status. Many carriers are sampled through families seen in genetic clinics. The first tested individual in a family is usually someone diagnosed with cancer at a relatively young age. Such study designs, therefore, tend to lead to an over-sampling of affected individuals, and standard analytical methods like Cox regression or case-control analysis may lead to biased estimates of the risk ratios [<xref ref-type="bibr" rid="B35">35</xref>
]. This can be illustrated by considering an individual affected at age <italic>t</italic>
. In a standard analysis of a cohort study or a case-control analysis, the SNP genotype for the individual will be compared with those of all individuals at risk at age <italic>t </italic>
or in a case-control analysis, with controls randomly sampled from all possible at risk individuals. This analysis leads to consistent estimates of the hazard ratio or odds ratio estimates. However, in the present design, mutation carriers are already selected on the basis of disease status (where affected individuals are over-sampled). If standard cohort analysis were applied to these data, it would lead to affected individuals at age <italic>t </italic>
being compared to unaffected carriers selected on the basis of their future disease status. If the genotype is associated with the disease, the risk estimate will be biased to zero because too many affected individuals (in whom the at-risk genotype is overrepresented) are included in the comparison group. Simulation studies have shown that this effect can be quite marked [<xref ref-type="bibr" rid="B35">35</xref>
]. To address this, a retrospective likelihood approach was previously proposed, which models the observed genotypes conditional on the disease phenotypes [<xref ref-type="bibr" rid="B36">36</xref>
]. For the current analyses we have extended this method to model the simultaneous effect of each SNP on more than one tumour subtype. We briefly describe this method for the analysis of associations with ER-positive and ER-negative breast cancer, but the same principles apply for the analysis of associations with other tumour characteristics.</p>
<p>We modelled the likelihood of the observed genotypes and tumour subtype conditional on the disease status, that is:</p>
<p><disp-formula id="bmcM1"><label>(1)</label>
<mml:math id="M1" name="bcr3052-i1" overflow="scroll"><mml:mrow><mml:munderover accentunder="false" accent="false"><mml:mrow><mml:mo mathsize="big">∏</mml:mo>
</mml:mrow>
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<mml:mn>1</mml:mn>
</mml:mrow>
<mml:mrow><mml:mi>n</mml:mi>
</mml:mrow>
</mml:munderover>
<mml:mi>P</mml:mi>
<mml:mfenced open="(" close=")"><mml:mrow><mml:msub><mml:mrow><mml:mi>g</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
<mml:mo class="MathClass-punc">,</mml:mo>
<mml:msub><mml:mrow><mml:mi>d</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
<mml:mo class="MathClass-rel">|</mml:mo>
<mml:mi>y</mml:mi>
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</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>n</mml:mi>
</mml:mrow>
</mml:munderover>
<mml:mfrac><mml:mrow><mml:mi>P</mml:mi>
<mml:mfenced open="(" close=")"><mml:mrow><mml:mrow><mml:mo class="MathClass-open">(</mml:mo>
<mml:mrow><mml:mi>y</mml:mi>
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<mml:mrow><mml:msub><mml:mrow><mml:mi>t</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
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</mml:mrow>
<mml:mo class="MathClass-punc">,</mml:mo>
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</mml:mrow>
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</mml:mrow>
</mml:msub>
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</mml:mrow>
</mml:mrow>
</mml:mfenced>
<mml:mi>P</mml:mi>
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<mml:mrow><mml:msub><mml:mrow><mml:mi>g</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
</mml:mrow>
<mml:mo class="MathClass-close">)</mml:mo>
</mml:mrow>
</mml:mrow>
<mml:mrow><mml:mi>P</mml:mi>
<mml:mfenced open="(" close=")"><mml:mrow><mml:mi>y</mml:mi>
<mml:mrow><mml:mo class="MathClass-open">(</mml:mo>
<mml:mrow><mml:msub><mml:mrow><mml:mi>t</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
</mml:mrow>
<mml:mo class="MathClass-close">)</mml:mo>
</mml:mrow>
</mml:mrow>
</mml:mfenced>
</mml:mrow>
</mml:mfrac>
</mml:mrow>
</mml:math>
</disp-formula>
</p>
<p>Where <italic>y</italic>
(<italic>t<sub>i</sub>
</italic>
) is the disease phenotype for individual <italic>i </italic>
at censoring age <italic>t<sub>i </sub>
</italic>
(breast cancer at age <italic>t<sub>i </sub>
</italic>
or unaffected at age <italic>t<sub>i</sub>
</italic>
), <italic>d<sub>i </sub>
</italic>
is the ER status (0 = negative, 1 = positive) and <italic>g<sub>i </sub>
</italic>
the observed genotype of individual <italic>i </italic>
(<italic>g<sub>i </sub>
</italic>
= 0, 1 or 2 minor alleles) and <italic>n </italic>
the number of subjects in the analysis. To allow for tumour characteristics we assumed that breast cancer consists of different disease subtypes, such that the total breast cancer incidence at age <italic>t<sub>i</sub>
</italic>
, <italic>λ</italic>
(<italic>t<sub>i</sub>
</italic>
), is the sum of the disease incidence for the subtypes, that is <italic>λ</italic>
(<italic>t<sub>i</sub>
</italic>
) = <italic>v</italic>
(<italic>t<sub>i</sub>
</italic>
) + <italic>μ</italic>
(<italic>t<sub>i</sub>
</italic>
), where <italic>v</italic>
(<italic>t<sub>i</sub>
</italic>
) is the incidence for ER-negative disease and <italic>μ</italic>
(<italic>t<sub>i</sub>
</italic>
) is the incidence of ER-positive disease. We assumed that the subtype-specific incidences depend on the underlying genotype through a Cox-proportional hazards model: <inline-formula><mml:math id="M2" name="bcr3052-i2" overflow="scroll"><mml:mi>ν</mml:mi>
<mml:mrow><mml:mo class="MathClass-open">(</mml:mo>
<mml:mrow><mml:msub><mml:mrow><mml:mi>t</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
</mml:msub>
</mml:mrow>
<mml:mo class="MathClass-close">)</mml:mo>
</mml:mrow>
<mml:mo class="MathClass-rel">=</mml:mo>
<mml:msub><mml:mrow><mml:mi>ν</mml:mi>
</mml:mrow>
<mml:mrow><mml:mn>0</mml:mn>
</mml:mrow>
</mml:msub>
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</mml:mrow>
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</mml:mrow>
</mml:msub>
</mml:mrow>
<mml:mo class="MathClass-close">)</mml:mo>
</mml:mrow>
<mml:mo class="qopname">exp</mml:mo>
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<mml:mrow><mml:msup><mml:mrow><mml:mi>β</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msup>
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</mml:mstyle>
</mml:mrow>
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</mml:mrow>
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</mml:msub>
</mml:mrow>
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</mml:mrow>
</mml:math>
</inline-formula>
and <inline-formula><mml:math id="M3" name="bcr3052-i3" overflow="scroll"><mml:mi>μ</mml:mi>
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</mml:mrow>
</mml:msub>
</mml:mrow>
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</mml:mrow>
<mml:mo class="MathClass-rel">=</mml:mo>
<mml:msub><mml:mrow><mml:mi>μ</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
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</mml:mrow>
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<mml:mrow><mml:msup><mml:mrow><mml:mi>γ</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msup>
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</mml:mstyle>
</mml:mrow>
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</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
</mml:msub>
</mml:mrow>
</mml:msub>
</mml:mrow>
<mml:mo class="MathClass-close">)</mml:mo>
</mml:mrow>
</mml:math>
</inline-formula>
where <italic>v</italic>
<sub>0</sub>
(<italic>t<sub>i</sub>
</italic>
) and <italic>μ</italic>
<sub>0</sub>
(<italic>t<sub>i</sub>
</italic>
) and are the baseline incidences for disease subtypes (ER-negative and ER-positive respectively), <inline-formula><mml:math id="M4" name="bcr3052-i4" overflow="scroll"><mml:msub><mml:mrow><mml:mstyle mathvariant="bold"><mml:mi>z</mml:mi>
</mml:mstyle>
</mml:mrow>
<mml:mrow><mml:msub><mml:mrow><mml:mi>g</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
</mml:msub>
</mml:mrow>
</mml:msub>
</mml:math>
</inline-formula>
is the genotype vector for individual <italic>i </italic>
and <bold><italic>β </italic>
</bold>
and <bold><italic>γ </italic>
</bold>
are the subtype specific genotype log-risk ratios (for ER-negative and ER-positive breast cancer respectively). The probabilities of developing ER-positive and ER-negative breast cancer conditional on the underlying genotype were assumed to be independent. We further assumed that, if tumour subtype is unknown, the information is missing at random with respect to genotype. Then for each individual:</p>
<p><disp-formula><mml:math id="M5" name="bcr3052-i5" overflow="scroll"><mml:mrow><mml:mi>P</mml:mi>
<mml:mfenced open="(" close=")"><mml:mrow><mml:mrow><mml:mo class="MathClass-open">(</mml:mo>
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<mml:mrow><mml:msub><mml:mrow><mml:mi>t</mml:mi>
</mml:mrow>
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</mml:mrow>
</mml:msub>
</mml:mrow>
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</mml:mrow>
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</mml:mrow>
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</mml:mrow>
</mml:msub>
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</mml:mrow>
</mml:mrow>
</mml:mfenced>
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</mml:mrow>
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</mml:mrow>
</mml:msub>
</mml:mrow>
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</mml:mrow>
<mml:mo class="qopname">exp</mml:mo>
<mml:mrow><mml:mo class="MathClass-open">(</mml:mo>
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</mml:mrow>
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</mml:mrow>
</mml:msup>
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</mml:mstyle>
</mml:mrow>
<mml:mrow><mml:msub><mml:mrow><mml:mi>g</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
</mml:msub>
</mml:mrow>
</mml:msub>
</mml:mrow>
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</mml:mrow>
</mml:mrow>
</mml:mfenced>
</mml:mrow>
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</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
</mml:msub>
<mml:mrow><mml:mo class="MathClass-open">(</mml:mo>
<mml:mrow><mml:mn>1</mml:mn>
<mml:mo class="MathClass-bin">-</mml:mo>
<mml:msub><mml:mrow><mml:mi>d</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>i</mml:mi>
</mml:mrow>
</mml:msub>
</mml:mrow>
<mml:mo class="MathClass-close">)</mml:mo>
</mml:mrow>
</mml:mrow>
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</disp-formula>
</p>
<p>were <italic>O<sub>i </sub>
</italic>
= 0 if unaffected and <italic>O<sub>i </sub>
</italic>
= 1 if affected. Thus, the above formulation allows use of all mutation carriers irrespective of whether the tumour subtype is observed or not. The baseline incidences for each disease subtype (<italic>v<sub>0</sub>
</italic>
(<italic>t<sub>i</sub>
</italic>
) and <italic>μ</italic>
<sub>0</sub>
(<italic>t<sub>i</sub>
</italic>
)) are unknown. However, it is possible to solve for those recursively by constraining the overall breast cancer incidence for mutation carriers <italic>λ</italic>
(<italic>t</italic>
), to agree with external estimates as previously demonstrated [<xref ref-type="bibr" rid="B37">37</xref>
,<xref ref-type="bibr" rid="B38">38</xref>
] and by imposing a further constraint on the ratio of the observed ER-positive to ER-negative breast cancers in each age group:<disp-formula><graphic xlink:href="bcr3052-i6.gif"></graphic>
</disp-formula>
</p>
<p>The likelihood in equation 1 can then be maximised jointly over the log-risk ratios <bold><italic>β </italic>
</bold>
and <bold><italic>γ</italic>
</bold>
, genotype frequencies <italic>P(g) </italic>
and the age and subtype-specific frequencies <italic>π</italic>
<sub>+</sub>
(<italic>t</italic>
) and <italic>π</italic>
<sub>-</sub>
(<italic>t</italic>
) This likelihood is based on the assumption that the ascertainment of mutation carriers is dependent on the overall disease phenotype (breast cancer) but not on tumour subtypes. This allows the subtype frequencies <italic>π</italic>
<sub>+</sub>
(<italic>t</italic>
) and <italic>π<sub>-</sub>
</italic>
(<italic>t</italic>
) to be estimated within the dataset. Relaxing this assumption and conditioning also on tumour subtype requires external estimates for the age and subtype-specific frequencies <italic>π</italic>
<sub>+</sub>
(<italic>t</italic>
) and <italic>π</italic>
<sub>-</sub>
(<italic>t</italic>
).</p>
<p>The effect of each SNP was modelled either as a per-allele HR (multiplicative model) or as separate HRs for heterozygotes and homozygotes, and these were estimated on the logarithmic scale. Heterogeneity in the hazard ratios between tumour subtypes was examined by fitting models where <italic>v</italic>
(<italic>t<sub>i</sub>
</italic>
) = <italic>v</italic>
<sub>0</sub>
(<italic>t<sub>i</sub>
</italic>
) exp (<italic>β</italic>
<sub>1<italic>g</italic>
</sub>
) and <italic>μ</italic>
(<italic>t<sub>i</sub>
</italic>
) = <italic>μ</italic>
<sub>0</sub>
(<italic>t<sub>i</sub>
</italic>
) exp (<italic>β</italic>
<sub>1 </sub>
+ <italic>β</italic>
<sub>2</sub>
)<italic>g</italic>
) with g = 0,1 and 2 (for 0, 1, 2 copies of the minor allele respectively) and testing for <italic>β</italic>
<sub>2 </sub>
= 0. Analyses were carried out with the pedigree-analysis software MENDEL [<xref ref-type="bibr" rid="B39">39</xref>
]. All analyses were stratified by country of residence and used calendar-year- and cohort-specific cancer incidences for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
[<xref ref-type="bibr" rid="B40">40</xref>
]. For this purpose, a stratified version of the retrospective likelihood (equation 1) was derived as described previously [<xref ref-type="bibr" rid="B36">36</xref>
]. Countries with small numbers of mutation carriers were grouped together. We used a robust variance-estimation approach to allow for the non-independence among related mutation carriers [<xref ref-type="bibr" rid="B41">41</xref>
].</p>
</sec>
<sec><title>Predicted breast cancer risks by ER status</title>
<p>Based on our results we computed the predicted absolute risk of developing ER-negative and ER-positive breast cancer for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers by the combined 12 SNP profile. For each individual we derived an empirical score, based on the per-allele log-relative hazard estimates for each genotype, which was of the form <inline-formula><mml:math id="M6" name="bcr3052-i7" overflow="scroll"><mml:munderover accentunder="false" accent="false"><mml:mrow><mml:mo class="MathClass-op">∑</mml:mo>
</mml:mrow>
<mml:mrow><mml:mi>j</mml:mi>
<mml:mo class="MathClass-rel">=</mml:mo>
<mml:mn>1</mml:mn>
</mml:mrow>
<mml:mrow><mml:mn>12</mml:mn>
</mml:mrow>
</mml:munderover>
<mml:msub><mml:mrow><mml:mi>β</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>j</mml:mi>
</mml:mrow>
</mml:msub>
<mml:msub><mml:mrow><mml:mi>g</mml:mi>
</mml:mrow>
<mml:mrow><mml:mi>j</mml:mi>
</mml:mrow>
</mml:msub>
</mml:math>
</inline-formula>
where <italic>β<sub>j </sub>
</italic>
is the per-allele log-hazard estimate for locus j and <italic>g<sub>j </sub>
</italic>
is the genotype at the same locus (taking values 0, 1 and 2). This assumes a multiplicative model for the combined SNP associations. This is a reasonable assumption given that previous analyses found no evidence of departure from the multiplicative model [<xref ref-type="bibr" rid="B35">35</xref>
]. Scores were calculated for ER-positive and ER-negative disease, separately for <italic>BRCA1</italic>
and <italic>BRCA2 </italic>
mutation carriers. The empirical distribution of the derived score was then used to compute the subtype specific incidence associated with each multilocus genotype as described previously [<xref ref-type="bibr" rid="B31">31</xref>
]. We reported the absolute risks of developing ER-specific breast cancer at the 5<sup>th</sup>
, 50<sup>th </sup>
and 95<sup>th </sup>
percentiles of the empirical distribution of the SNP profile.</p>
</sec>
</sec>
<sec><title>Results</title>
<p>A total of 11,421 <italic>BRCA1 </italic>
and 7,080 <italic>BRCA2 </italic>
mutation carriers from 36 studies had been successfully genotyped for at least one of the12 SNPs and were eligible for inclusion in these analyses. 9,815 <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers were censored at a first invasive breast cancer diagnosis, of whom 4,310 had information on either ER or PR (Table <xref ref-type="table" rid="T1">1</xref>
).</p>
<sec><title>Associations with ER status - BRCA1 mutation carriers</title>
<p>There were significant differences in the HR for ER-positive and ER-negative disease for <italic>BRCA1 </italic>
mutation carriers for two SNPs (Table <xref ref-type="table" rid="T2">2</xref>
). The <italic>FGFR2 </italic>
SNP rs2981582 exhibited the clearest difference with a strong association for ER-positive disease but not ER-negative disease (per allele HR = 1.35, 95% CI: 1.17 to 1.56, for ER-positive compared with HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, <italic>P</italic>
-heterogeneity = 6.5 × 10<sup>-6</sup>
). The <italic>SLC4A7/NEK10 </italic>
SNP rs4973768 also exhibited a similar pattern (ER-positive: per-allele HR = 1.17, 95% CI: 1.03 to 1.133, compared with ER-negative: per-allele HR = 0.99, 95% CI: 0.93 to 1.06, <italic>P</italic>
-heterogeneity = 0.027). Although there was no significant evidence of differences between the HRs for ER-positive and ER-negative breast cancer, the <italic>TOX3/TNRC9 </italic>
SNP rs3803662 was significantly associated with the risk of ER-positive disease (per-allele HR = 1.25, 95% CI: 1.06 to .46, <italic>P</italic>
-trend = 0.0062) but not with risk for ER-negative breast cancer (per-allele HR = 1.05, 95% CI: 0.97 to 1.13, <italic>P</italic>
-trend = 0.21). <italic>LSP1 </italic>
SNP rs3817198 was associated with the risk of ER-negative breast cancer (per-allele HR = 1.07, 95% CI: 1.00 to 1.07, <italic>P</italic>
-trend = 0.047) but not with risk of ER-positive breast cancer (per-allele HR = 1.07, 95% CI: 0.93 to 1.22, <italic>P</italic>
-trend = 0.33, <italic>P</italic>
-het = 0.98). The 6q25.1 SNP rs2046210 near <italic>ESR1 </italic>
was associated with the risk for both ER-negative (per-allele HR = 1.19, 95% CI: 1.11 to 1.27, <italic>P</italic>
-trend = 2.4 × 10<sup>-7</sup>
) and ER-positive (per-allele HR = 1.14, 95% CI: 1.01 to 1.30, <italic>P</italic>
-trend = 0.043) breast cancer. There was no significant evidence of association with either ER-negative or ER-positive breast cancer for any of the other SNPs, although the HR estimates tended to be higher for ER-positive breast cancer (for example, SNPs rs13387042 at 2q35 and rs13281615 at 8q24).</p>
<table-wrap id="T2" position="float"><label>Table 2</label>
<caption><p>Genotype and per-allele hazard ratio estimates by estrogen receptor status for <italic>BRCA1 </italic>
mutation carriers</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center">Genotype</th>
<th align="center"><bold>Unaffected</bold>
,</th>
<th align="center" colspan="3">Affected by subtype, N (%)</th>
<th align="center" colspan="3">ER-</th>
<th align="center" colspan="3">ER+</th>
<th align="center"><italic>P</italic>
-het</th>
</tr>
<tr><th></th>
<th align="center">N (%)</th>
<th align="center">ER-</th>
<th align="center">ER+</th>
<th align="center">Unknown</th>
<th align="center">HR</th>
<th align="center">95% CI</th>
<th align="center"><italic>P-trend</italic>
</th>
<th align="center">HR</th>
<th align="center">95% CI</th>
<th align="center"><italic>P-trend</italic>
</th>
<th></th>
</tr>
</thead>
<tbody><tr><td align="center"><italic>FGFR2 rs2981582</italic>
</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">1301 (36.2)</td>
<td align="center">447 (40.0)</td>
<td align="center">104 (29.6)</td>
<td align="center">869 (35.1)</td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GA</td>
<td align="center">1,721 (47.9)</td>
<td align="center">516 (46.2)</td>
<td align="center">166 (47.3)</td>
<td align="center">1190 (48.1)</td>
<td align="center"><bold>0.93</bold>
</td>
<td align="center"><bold>0.83 to 1.03</bold>
</td>
<td></td>
<td align="center"><bold>1.24</bold>
</td>
<td align="center"><bold>0.98 to 1.57</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">573 (15.9)</td>
<td align="center">154 (13.8)</td>
<td align="center">81 (23.1)</td>
<td align="center">416 (16.8)</td>
<td align="center"><bold>0.82</bold>
</td>
<td align="center"><bold>0.70 to 0.96</bold>
</td>
<td></td>
<td align="center"><bold>1.85</bold>
</td>
<td align="center"><bold>1.40 to 2.44</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center"><bold>0.91</bold>
</td>
<td align="center"><bold>0.85 to 0.98</bold>
</td>
<td align="center"><bold>0.01</bold>
</td>
<td align="center"><bold>1.35</bold>
</td>
<td align="center"><bold>1.17 to 1.56</bold>
</td>
<td align="center"><bold>4 × 10<sup>-5</sup>
</bold>
</td>
<td align="center"><bold>6.5 ×10<sup>-6</sup>
</bold>
</td>
</tr>
<tr><td align="center"><italic>TOX3/TNRC9 rs3803662</italic>
</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">1,811 (52.0)</td>
<td align="center">545 (49.5)</td>
<td align="center">154 (45.7)</td>
<td align="center">1195 (50.2)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CT</td>
<td align="center">1,405 (40.3)</td>
<td align="center">461 (41.8)</td>
<td align="center">143 (42.4)</td>
<td align="center">987 (41.5)</td>
<td align="center">1.06</td>
<td align="center">0.96 to 1.18</td>
<td></td>
<td align="center"><bold>1.20</bold>
</td>
<td align="center"><bold>0.97 to 1.50</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">269 (7.7)</td>
<td align="center">96 (8.7)</td>
<td align="center">40 (11.9)</td>
<td align="center">199 (8.4)</td>
<td align="center">1.09</td>
<td align="center">0.90 to 1.31</td>
<td></td>
<td align="center"><bold>1.61</bold>
</td>
<td align="center"><bold>1.14 to 2.27</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.05</td>
<td align="center">0.97 to 1.13</td>
<td align="center">0.21</td>
<td align="center"><bold>1.25</bold>
</td>
<td align="center"><bold>1.06 to 1.46</bold>
</td>
<td align="center"><bold>0.0062</bold>
</td>
<td align="center">0.07</td>
</tr>
<tr><td align="center"><italic>MAP3K1 </italic>
rs889312</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">1,858 (49.6)</td>
<td align="center">569 (49.7)</td>
<td align="center">186 (52.1)</td>
<td align="center">1319 (51.6)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AC</td>
<td align="center">1,552 (41.4)</td>
<td align="center">480 (41.9)</td>
<td align="center">136 (38.1)</td>
<td align="center">987 (38.6)</td>
<td align="center">0.97</td>
<td align="center">0.87 to 1.07</td>
<td></td>
<td align="center">0.86</td>
<td align="center">0.69 to 1.06</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">336 (9.0)</td>
<td align="center">97 (8.5)</td>
<td align="center">35 (9.8)</td>
<td align="center">250 (9.8)</td>
<td align="center">0.97</td>
<td align="center">0.81 to 1.16</td>
<td></td>
<td align="center">0.97</td>
<td align="center">0.69 to 1.35</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.98</td>
<td align="center">0.91 to 1.06</td>
<td align="center">0.56</td>
<td align="center">0.97</td>
<td align="center">0.83 to 1.13</td>
<td align="center">0.69</td>
<td align="center">0.92</td>
</tr>
<tr><td align="center"><italic>LSP1 </italic>
rs3817198</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">1,894 (47.4)</td>
<td align="center">652 (45.4)</td>
<td align="center">195 (44.5)</td>
<td align="center">1205 (43.7)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TC</td>
<td align="center">1,680 (42.0)</td>
<td align="center">629 (43.8)</td>
<td align="center">197 (45.0)</td>
<td align="center">1239 (44.9)</td>
<td align="center">1.09</td>
<td align="center">0.99 to 1.20</td>
<td></td>
<td align="center">1.11</td>
<td align="center">0.92 to 1.35</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">422 (10.6)</td>
<td align="center">154 (10.7)</td>
<td align="center">46 (10.5)</td>
<td align="center">315 (11.4)</td>
<td align="center">1.13</td>
<td align="center">0.97 to 1.33</td>
<td></td>
<td align="center">1.10</td>
<td align="center">0.80 to 1.50</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center"><bold>1.07</bold>
</td>
<td align="center"><bold>1.00 to 1.15</bold>
</td>
<td align="center"><bold>0.047</bold>
</td>
<td align="center">1.07</td>
<td align="center">0.93 to 1.22</td>
<td align="center">0.33</td>
<td align="center">0.98</td>
</tr>
<tr><td align="center">2q35 rs13387042</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">924 (24.0)</td>
<td align="center">301 (22.1)</td>
<td align="center">93 (22.2)</td>
<td align="center">576 (21.4)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GA</td>
<td align="center">1,855 (48.3)</td>
<td align="center">723 (53.1)</td>
<td align="center">194 (46.3)</td>
<td align="center">1370 (50.9)</td>
<td align="center"><bold>1.17</bold>
</td>
<td align="center"><bold>1.04 to 1.32</bold>
</td>
<td></td>
<td align="center">1.02</td>
<td align="center">0.81 to 1.30</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">1,064 (27.7)</td>
<td align="center">338 (24.8)</td>
<td align="center">132 (31.5)</td>
<td align="center">745 (27.7)</td>
<td align="center">0.96</td>
<td align="center">0.84 to 1.11</td>
<td></td>
<td align="center">1.25</td>
<td align="center">0.97 to 1.62</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.98</td>
<td align="center">0.91 to 1.04</td>
<td align="center">0.48</td>
<td align="center">1.13</td>
<td align="center">0.99 to 1.28</td>
<td align="center">0.075</td>
<td align="center">0.065</td>
</tr>
<tr><td align="center">8q24 rs13281615</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">1,319 (32.8)</td>
<td align="center">502 (35.9)</td>
<td align="center">143 (33.7)</td>
<td align="center">897 (32.5)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.0</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AG</td>
<td align="center">2,008 (50.0)</td>
<td align="center">657 (47.0)</td>
<td align="center">198 (46.7)</td>
<td align="center">1,364 (49.5)</td>
<td align="center">0.98</td>
<td align="center">0.88 to 1.08</td>
<td></td>
<td align="center">0.97</td>
<td align="center">0.79 to 1.19</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">691 (17.9)</td>
<td align="center">238 (17.0)</td>
<td align="center">83 (19.6)</td>
<td align="center">496 (18.0)</td>
<td align="center">1.00</td>
<td align="center">0.87 to 1.16</td>
<td></td>
<td align="center">1.17</td>
<td align="center">0.89 to 1.53</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td align="center">0.93 to 1.07</td>
<td align="center">0.93</td>
<td align="center">1.06</td>
<td align="center">0.93 to 1.22</td>
<td align="center">0.38</td>
<td align="center">0.43</td>
</tr>
<tr><td align="center" colspan="2">SLC4A7/NEK10 rs4973768</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">1,148 (26.2)</td>
<td align="center">406 (27.2)</td>
<td align="center">103 (22.2)</td>
<td align="center">691 (24.7)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CT</td>
<td align="center">2,205 (50.4)</td>
<td align="center">736 (49.3)</td>
<td align="center">235 (50.5)</td>
<td align="center">1,399 (50.1)</td>
<td align="center">0.98</td>
<td align="center">0.88 to 1.08</td>
<td></td>
<td align="center">1.20</td>
<td align="center">0.96 to 1.51</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">1,024 (23.4)</td>
<td align="center">350 (23.5)</td>
<td align="center">127 (27.3)</td>
<td align="center">703 (25.2)</td>
<td align="center">0.99</td>
<td align="center">0.87 to 1.12</td>
<td></td>
<td align="center"><bold>1.38</bold>
</td>
<td align="center"><bold>1.07 to 1.77</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.99</td>
<td align="center">0.93 to 1.06</td>
<td align="center">0.83</td>
<td align="center"><bold>1.17</bold>
</td>
<td align="center"><bold>1.03 to 1.33</bold>
</td>
<td align="center"><bold>0.013</bold>
</td>
<td align="center"><bold>0.027</bold>
</td>
</tr>
<tr><td align="center" colspan="2">STXBP4/COX11 rs6504950</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">2,346 (53.1)</td>
<td align="center">814 (53.2)</td>
<td align="center">252 (52.9)</td>
<td align="center">1,502 (53.1))</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GA</td>
<td align="center">1,737 (39.3)</td>
<td align="center">593 (37.8)</td>
<td align="center">191 (40.1)</td>
<td align="center">1,127 (39.8)</td>
<td align="center">1.00</td>
<td align="center">0.91 to 1.10</td>
<td></td>
<td align="left">1.03</td>
<td align="center">0.86 to 1.24</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">333 (7.5)</td>
<td align="center">122 (8.0)</td>
<td align="center">33 (6.9)</td>
<td align="center">200 (7.1)</td>
<td align="center">1.04</td>
<td align="center">0.88 to 1.23</td>
<td></td>
<td align="center">0.94</td>
<td align="center">0.65 to 1.34</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.01</td>
<td align="center">0.94 to 1.09</td>
<td align="center">0.77</td>
<td align="center">1.00</td>
<td align="center">0.87 to 1.15</td>
<td align="center">0.97</td>
<td align="center">0.87</td>
</tr>
<tr><td align="center" colspan="2">5p12 rs10941679</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">2,211 (55.8)</td>
<td align="center">815 (57.3)</td>
<td align="center">271 (61.0)</td>
<td align="center">1,529 (56.5)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AG</td>
<td align="center">1,472 (37.1)</td>
<td align="center">517 (36.4)</td>
<td align="center">145 (32.7)</td>
<td align="center">1,001 (37.0)</td>
<td align="center">0.99</td>
<td align="center">0.90 to 1.09</td>
<td></td>
<td align="center">0.84</td>
<td align="center">0.69 to 1.02</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">280 (7.1)</td>
<td align="center">90 (6.3)</td>
<td align="center">28 (6.3)</td>
<td align="center">177 (6.5)</td>
<td align="center">0.89</td>
<td align="center">0.73 to 1.08</td>
<td></td>
<td align="center">0.84</td>
<td align="center">0.58 to 1.20</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.97</td>
<td align="center">0.90 to 1.04</td>
<td align="center">0.39</td>
<td align="center">0.88</td>
<td align="center">0.75 to 1.02</td>
<td align="center">0.08</td>
<td align="center">0.26</td>
</tr>
<tr><td align="center">6q25.1 - rs2046210</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">1,886 (43.3)</td>
<td align="center">567 (38.2)</td>
<td align="center">158 (36.0)</td>
<td align="center">1,007 (37.0)</td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TC</td>
<td align="center">1,919 (44.1)</td>
<td align="center">718 (48.3)</td>
<td align="center">232 (52.9)</td>
<td align="center">1,305 (48.0)</td>
<td align="center"><bold>1.21</bold>
</td>
<td align="center"><bold>1.10 to 1.33</bold>
</td>
<td></td>
<td align="center"><bold>1.37</bold>
</td>
<td align="center"><bold>1.13 to 1.67</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">547 (12.6)</td>
<td align="center">201 (13.5)</td>
<td align="center">49 (11.2)</td>
<td align="center">409 (15.0)</td>
<td align="center"><bold>1.39</bold>
</td>
<td align="center"><bold>1.21 to 1.59</bold>
</td>
<td></td>
<td align="center"><bold>1.11</bold>
</td>
<td align="center"><bold>0.81 to 1.53</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center"><bold>1.19</bold>
</td>
<td align="center"><bold>1.11 to 1.27</bold>
</td>
<td align="center"><bold>2.4 × 10<sup>-7</sup>
</bold>
</td>
<td align="center"><bold>1.14</bold>
</td>
<td align="center"><bold>1.01 to 1.30</bold>
</td>
<td align="center"><bold>0.043</bold>
</td>
<td align="center">0.60</td>
</tr>
<tr><td align="center">1p11.2 - rs11249433</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">1,491 (34.1)</td>
<td align="center">506 (33.7)</td>
<td align="center">144 (32.4)</td>
<td align="center">973 (35.1)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CT</td>
<td align="center">2,133 (48.7)</td>
<td align="center">745 (49.7)</td>
<td align="center">245 (55.2)</td>
<td align="center">1,342 (48.5)</td>
<td align="center">0.97</td>
<td align="center">0.88 to 1.07</td>
<td></td>
<td align="center">1.10</td>
<td align="center">0.90 to 1.34</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">752 (17.2)</td>
<td align="center">248 (16.5)</td>
<td align="center">55 (12.4)</td>
<td align="center">455 (16.4)</td>
<td align="center">0.99</td>
<td align="center">0.87 to 1.13</td>
<td></td>
<td align="center">0.76</td>
<td align="center">0.56 to 1.03</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.99</td>
<td align="center">0.93 to 1.06</td>
<td align="center">0.79</td>
<td align="center">0.92</td>
<td align="center">0.81 to 1.05</td>
<td align="center">0.22</td>
<td align="center">0.35</td>
</tr>
<tr><td align="center" colspan="2"><bold><italic>RAD51L1 </italic>
- rs999737/rs10483813</bold>
</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC/TT</td>
<td align="center">2,335 (61.5)</td>
<td align="center">760 (64.1)</td>
<td align="center">212 (62.5)</td>
<td align="center">1,551 (62.5)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TC/AT</td>
<td align="center">1,294 (34.1)</td>
<td align="center">370 (31.2)</td>
<td align="center">113 (33.3)</td>
<td align="center">819 (33.0)</td>
<td align="center">0.92</td>
<td align="center">0.83 to 1.03</td>
<td></td>
<td align="center">1.00</td>
<td align="center">0.80 to 1.24</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT/AA</td>
<td align="center">170 (4.5)</td>
<td align="center">56 (4.7)</td>
<td align="center">14 (4.1)</td>
<td align="center">110 (4.4)</td>
<td align="center">1.02</td>
<td align="center">0.81 to 1.28</td>
<td></td>
<td align="center">0.93</td>
<td align="center">0.56 to 1.56</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">per allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.96</td>
<td align="center">0.88 to 1.04</td>
<td align="center">0.34</td>
<td align="center">0.98</td>
<td align="center">0.82 to 1.18</td>
<td align="center">0.87</td>
<td align="center">0.81</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p><italic>P</italic>
-het, Heterogeneity <italic>P</italic>
-value; ER-, estrogen receptor negative; ER+, estrogen receptor positive</p>
</table-wrap-foot>
</table-wrap>
</sec>
<sec><title>Associations with ER status - BRCA2 mutation carriers</title>
<p>Only SNP rs2046210 at 6q25.1 exhibited differential associations between ER-positive and ER-negative breast cancer for <italic>BRCA2 </italic>
mutation carriers (<italic>P</italic>
-heterogeneity = 0.045, Table <xref ref-type="table" rid="T3">3</xref>
). The per-allele HR for ER-negative disease was estimated to be 1.17 (95% CI: 0.99 to 1.38) whereas the per-allele HR for ER-positive breast cancer was 0.97 (95% CI: 0.89 to 1.05). Although there were no significant differences in the associations between the two types of disease for <italic>BRCA2 </italic>
mutation carriers, the HR estimates for ER-positive disease tended to be larger compared to ER-negative breast cancer. SNPs at/near <italic>FGFR2, TOX3/TNRC9, MAP3K1, LSP1</italic>
, 2q35<italic>, SLC4A7/NEK10</italic>
, 5p12 and 1p11.2 were associated with ER-positive breast cancer for <italic>BRCA2 </italic>
mutation carriers (using either a per-allele or 2 df genotype test). The strongest associations were for the <italic>FGFR2 </italic>
rs2981582 SNP (HR for ER-positive breast cancer = 1.35, 95% CI: 1.23 to 1.48, <italic>P</italic>
-trend = 1.4 × 10<sup>-10</sup>
) and <italic>TOX3/TNRC9 </italic>
SNP rs3803662 (HR for ER-positive breast cancer = 1.28. 95% CI: 1.16 to 1.41, <italic>P</italic>
-trend = 1.5 × 10<sup>-6</sup>
). Only SNPs at or near <italic>MAP3K1, STXBP4/COX11 </italic>
and 6q25.1 were associated with the risk of ER-negative breast cancer for <italic>BRCA2 </italic>
mutation carriers.</p>
<table-wrap id="T3" position="float"><label>Table 3</label>
<caption><p>Genotype and per-allele hazard ratio estimates by estrogen receptor status for <italic>BRCA2 </italic>
mutation carriers</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center">Genotype</th>
<th align="center"><bold>Unaffected</bold>
,</th>
<th align="center" colspan="3">Affected by subtype, N (%)</th>
<th align="center" colspan="3">ER-</th>
<th align="center" colspan="3">ER+</th>
<th align="center"><italic>P</italic>
-het</th>
</tr>
<tr><th></th>
<th align="center">N (%)</th>
<th align="center">ER-</th>
<th align="center">ER+</th>
<th align="center">Unknown</th>
<th align="center">HR</th>
<th align="center">95%CI</th>
<th align="center"><italic>P-trend</italic>
</th>
<th align="center">HR</th>
<th align="center">95% CI</th>
<th align="center"><italic>P-trend</italic>
</th>
<th></th>
</tr>
</thead>
<tbody><tr><td align="center"><italic>FGFR2 rs2981582</italic>
</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">794 (37.8)</td>
<td align="center">86 (32.7)</td>
<td align="center">248 (29.5)</td>
<td align="center">457 (29.8)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GA</td>
<td align="center">987 (47.0)</td>
<td align="center">137 (52.1)</td>
<td align="center">419 (49.8)</td>
<td align="center">755 (49.3)</td>
<td align="center">1.28</td>
<td align="center">0.99 to 1.67</td>
<td></td>
<td align="center"><bold>1.35</bold>
</td>
<td align="center"><bold>1.17 to 1.55</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">321 (15.3)</td>
<td align="center">40 (15.2)</td>
<td align="center">174 (20.7)</td>
<td align="center">320 (20.9)</td>
<td align="center">1.23</td>
<td align="center">0.85 to 1.78</td>
<td></td>
<td align="center"><bold>1.81</bold>
</td>
<td align="center"><bold>1.51 to 2.18</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.14</td>
<td align="center">0.97 to 1.35</td>
<td align="center">0.12</td>
<td align="center"><bold>1.35</bold>
</td>
<td align="center"><bold>1.23 to 1.48</bold>
</td>
<td align="center"><bold>1.4 × 10<sup>-10</sup>
</bold>
</td>
<td align="center">0.097</td>
</tr>
<tr><td align="center" colspan="2"><italic>TOX3/TNRC9 rs3803662</italic>
</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">1,088 (53.4)</td>
<td align="center">136 (53.3)</td>
<td align="center">377 (46.3)</td>
<td align="center">702 (48.2)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CT</td>
<td align="center">792 (38.9)</td>
<td align="center">96 (37.7)</td>
<td align="center">361 (44.3)</td>
<td align="center">604 (41.5)</td>
<td align="center">0.98</td>
<td align="center">0.75 to 1.27</td>
<td></td>
<td align="center"><bold>1.33</bold>
</td>
<td align="center"><bold>1.17 to 1.53</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">157 (7.7)</td>
<td align="center">23 (9.0)</td>
<td align="center">77 (9.5)</td>
<td align="center">150 (10.3)</td>
<td align="center">1.27</td>
<td align="center">0.83 to 1.93</td>
<td></td>
<td align="center"><bold>1.54</bold>
</td>
<td align="center"><bold>1.22 to 1.95</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.06</td>
<td align="center">0.88 to 1.29</td>
<td align="center">0.53</td>
<td align="center"><bold>1.28</bold>
</td>
<td align="center"><bold>1.16 to 1.41</bold>
</td>
<td align="center"><bold>1.5 × 10<sup>-6</sup>
</bold>
</td>
<td align="center">0.11</td>
</tr>
<tr><td align="center"><italic>MAP3K1 </italic>
rs889312</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">1,107 (51.1)</td>
<td align="center">121 (45.7)</td>
<td align="center">430 (50.3)</td>
<td align="center">746 (47.7)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AC</td>
<td align="center">888 (41.0)</td>
<td align="center">120 (45.3)</td>
<td align="center">349 (40.8)</td>
<td align="center">646 (41.3)</td>
<td align="center">1.23</td>
<td align="center">0.96 to 1.59</td>
<td></td>
<td align="center">1.03</td>
<td align="center">0.90 to 1.17</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">170 (7.9)</td>
<td align="center">24 (9.1)</td>
<td align="center">76 (8.9)</td>
<td align="center">172 (11.0)</td>
<td align="center">1.42</td>
<td align="center">0.93 to 2.16</td>
<td></td>
<td align="center"><bold>1.29</bold>
</td>
<td align="center"><bold>1.03 to 1.62</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center"><bold>1.21</bold>
</td>
<td align="center"><bold>1.01 to 1.45</bold>
</td>
<td align="center"><bold>0.039</bold>
</td>
<td align="center">1.09</td>
<td align="center">0.99 to 1.21</td>
<td align="center">0.08</td>
<td align="center">0.35</td>
</tr>
<tr><td align="center"><italic>LSP1 </italic>
rs3817198</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">1,075 (46.1)</td>
<td align="center">142 (44.4)</td>
<td align="center">429 (42.0)</td>
<td align="center">718 (42.7)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TC</td>
<td align="center">1,005 (43.1)</td>
<td align="center">146 (45.6)</td>
<td align="center">466 (45.6)</td>
<td align="center">759 (45.2)</td>
<td align="center">1.08</td>
<td align="center">0.86 to 1.36</td>
<td></td>
<td align="center"><bold>1.14</bold>
</td>
<td align="center"><bold>1.01 to 1.29</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">252 (10.8)</td>
<td align="center">32 (10.0)</td>
<td align="center">127 (12.4)</td>
<td align="center">203 (12.1)</td>
<td align="center">1.02</td>
<td align="center">0.68 to 1.51</td>
<td></td>
<td align="center"><bold>1.39</bold>
</td>
<td align="center"><bold>1.14 to 1.70</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.03</td>
<td align="center">0.87 to 1.22</td>
<td align="center">0.70</td>
<td align="center"><bold>1.17</bold>
</td>
<td align="center"><bold>1.07 to 1.28</bold>
</td>
<td align="center"><bold>5.5 × 10<sup>-4</sup>
</bold>
</td>
<td align="center">0.20</td>
</tr>
<tr><td align="center">2q35 rs13387042</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">571 (25.3)</td>
<td align="center">71 (23.0)</td>
<td align="center">216 (22.0)</td>
<td align="center">382 (23.1)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GA</td>
<td align="center">1,080 (47.8)</td>
<td align="center">156 (50.5)</td>
<td align="center">500 (50.8)</td>
<td align="center">809 (48.8)</td>
<td align="center">1.12</td>
<td align="center">0.85 to 1.47</td>
<td></td>
<td align="center"><bold>1.18</bold>
</td>
<td align="center"><bold>1.01 to 1.36</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">608 (26.9)</td>
<td align="center">82 (26.5)</td>
<td align="center">268 (27.2)</td>
<td align="center">466 (28.1)</td>
<td align="center">1.06</td>
<td align="center">0.78 to 1.45</td>
<td></td>
<td align="center">1.13</td>
<td align="center">0.95 to 1.34</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.03</td>
<td align="center">0.87 to 1.19</td>
<td align="center">0.71</td>
<td align="center">1.06</td>
<td align="center">0.97 to 1.15</td>
<td align="center">0.20</td>
<td align="center">0.75</td>
</tr>
<tr><td align="center">8q24 rs13281615</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">794 (34.1)</td>
<td align="center">99 (31.6)</td>
<td align="center">317 (31.7)</td>
<td align="center">524 (31.3)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AG</td>
<td align="center">1,156 (49.6)</td>
<td align="center">165 (52.7)</td>
<td align="center">511 (51.1)</td>
<td align="center">837 (49.9)</td>
<td align="center">1.08</td>
<td align="center">0.85 to 1.38</td>
<td></td>
<td align="center">1.05</td>
<td align="center">0.92 to 1.21</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">382 (16.4)</td>
<td align="center">49 (15.7)</td>
<td align="center">172 (17.2)</td>
<td align="center">315 (18.8)</td>
<td align="center">1.05</td>
<td align="center">0.75 to 1.46</td>
<td></td>
<td align="center">1.13</td>
<td align="center">0.94 to 1.35</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.04</td>
<td align="center">0.89 to 1.21</td>
<td align="center">0.66</td>
<td align="center">1.06</td>
<td align="center">0.97 to 1.16</td>
<td align="center">0.19</td>
<td align="center">0.80</td>
</tr>
<tr><td align="center" colspan="2">SLC4A7/NEK10 rs4973768</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">669 (26.5)</td>
<td align="center">82 (24.9)</td>
<td align="center">251 (22.6)</td>
<td align="center">401 (23.5)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CT</td>
<td align="center">1,241 (49.1)</td>
<td align="center">164 (49.9)</td>
<td align="center">546 (49.4)</td>
<td align="center">829 (48.7)</td>
<td align="center">1.05</td>
<td align="center">0.81 to 1.36</td>
<td></td>
<td align="center"><bold>1.14</bold>
</td>
<td align="center"><bold>0.99 to 1.31</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">618 (24.5)</td>
<td align="center">83 (25.2)</td>
<td align="center">311 (28.0)</td>
<td align="center">474 (27.8)</td>
<td align="center">1.04</td>
<td align="center">0.77 to 1.41</td>
<td></td>
<td align="center"><bold>1.27</bold>
</td>
<td align="center"><bold>1.08 to 1.50</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.02</td>
<td align="center">0.88 to 1.19</td>
<td align="center">0.78</td>
<td align="center"><bold>1.13</bold>
</td>
<td align="center"><bold>1.04 to 1.22</bold>
</td>
<td align="center"><bold>0.0043</bold>
</td>
<td align="center">0.25</td>
</tr>
<tr><td align="center" colspan="2">STXBP4/COX11 rs6504950</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">1,420 (55.6)</td>
<td align="center">171 (51.0)</td>
<td align="center">601 (53.1)</td>
<td align="center">896 (52.5)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GA</td>
<td align="center">951 (37.2)</td>
<td align="center">145 (43.3)</td>
<td align="center">444 (39.3)</td>
<td align="center">684 (40.1)</td>
<td align="center"><bold>1.27</bold>
</td>
<td align="center"><bold>1.03 to 1.58</bold>
</td>
<td></td>
<td align="center">1.09</td>
<td align="center">0.97 to 1.23</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">184 (7.2)</td>
<td align="center">19 (5.7)</td>
<td align="center">86 (7.6)</td>
<td align="center">127 (7.4)</td>
<td align="center">0.84</td>
<td align="center">0.54 to 1.30</td>
<td></td>
<td align="center">1.08</td>
<td align="center">0.87 to 1.34</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.07</td>
<td align="center">0.92 to 1.25</td>
<td align="center">0.36</td>
<td align="center">1.06</td>
<td align="center">0.97 to 1.16</td>
<td align="center">0.19</td>
<td align="center">0.91</td>
</tr>
<tr><td align="center">5p12 rs10941679</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AA</td>
<td align="center">1,372 (58.6)</td>
<td align="center">176 (54.8)</td>
<td align="center">584 (54.8)</td>
<td align="center">924 (56.3)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">AG</td>
<td align="center">824 (35.2)</td>
<td align="center">122 (38.0)</td>
<td align="center">425 (39.9)</td>
<td align="center">622 (37.9)</td>
<td align="center">1.08</td>
<td align="center">0.86 to 1.37</td>
<td></td>
<td align="center"><bold>1.15</bold>
</td>
<td align="center"><bold>1.01 to 1.30</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">GG</td>
<td align="center">146 (6.2)</td>
<td align="center">23 (7.2)</td>
<td align="center">57 (5.4)</td>
<td align="center">94 (5.7)</td>
<td align="center">1.25</td>
<td align="center">0.82 to 1.91</td>
<td></td>
<td align="center">0.94</td>
<td align="center">0.73 to 1.22</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.10</td>
<td align="center">0.92 to 1.31</td>
<td align="center">0.28</td>
<td align="center">1.06</td>
<td align="center">0.96 to 1.17</td>
<td align="center">0.23</td>
<td align="center">0.70</td>
</tr>
<tr><td align="center">6q25.1 - rs2046210</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">985 (39.8)</td>
<td align="center">121 (39.2)</td>
<td align="center">466 (42.1)</td>
<td align="center">634 (37.7)</td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TC</td>
<td align="center">1,165 (47.1)</td>
<td align="center">132 (42.7)</td>
<td align="center">499 (45.1)</td>
<td align="center">802 (47.7)</td>
<td align="center"><bold>0.99</bold>
</td>
<td align="center"><bold>0.78 to 1.12</bold>
</td>
<td></td>
<td align="center">0.96</td>
<td align="center">0.85 to 1.08</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">324 (13.1)</td>
<td align="center">56 (18.1)</td>
<td align="center">141 (12.8)</td>
<td align="center">247 (14.7)</td>
<td align="center"><bold>1.47</bold>
</td>
<td align="center"><bold>1.08 to 2.01</bold>
</td>
<td></td>
<td align="center">0.94</td>
<td align="center">0.78 to 1.12</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.17</td>
<td align="center">0.99 to 1.38</td>
<td align="center">0.059</td>
<td align="center">0.97</td>
<td align="center">0.89 to 1.05</td>
<td align="center">0.41</td>
<td align="center"><bold>0.045</bold>
</td>
</tr>
<tr><td align="center">1p11.2 - rs11249433</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT</td>
<td align="center">895 (35.9)</td>
<td align="center">107 (33.6)</td>
<td align="center">345 (31.4)</td>
<td align="center">599 (34.7)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center"><bold>1.00</bold>
</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CT</td>
<td align="center">1,226 (49.2)</td>
<td align="center">160 (50.3)</td>
<td align="center">553 (50.3)</td>
<td align="center">843 (48.9)</td>
<td align="center">1.00</td>
<td align="center">0.79 to 1.28</td>
<td></td>
<td align="left"><bold>1.08</bold>
</td>
<td align="center"><bold>0.96 to 1.23</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">CC</td>
<td align="center">371 (14.9)</td>
<td align="center">51 (16.0)</td>
<td align="center">202 (18.4)</td>
<td align="center">282 (16.4)</td>
<td align="center">1.00</td>
<td align="center">0.73 to 1.40</td>
<td></td>
<td align="center"><bold>1.27</bold>
</td>
<td align="center"><bold>1.08 to 1.50</bold>
</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td align="center">0.86 to 1.17</td>
<td align="center">0.98</td>
<td align="center"><bold>1.12</bold>
</td>
<td align="center"><bold>1.03 to 1.22</bold>
</td>
<td align="center"><bold>0.0065</bold>
</td>
<td align="center">0.23</td>
</tr>
<tr><td align="center" colspan="2"><bold><italic>RAD51L1 </italic>
- rs999737/rs10483813</bold>
</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr><td align="center"><italic>BRCA1</italic>
</td>
<td align="left">CC/TT</td>
<td align="center">1,368 (59.5)</td>
<td align="center">167 (59.0)</td>
<td align="center">589 (61.4)</td>
<td align="center">1,000 (62.0)</td>
<td align="center">1.00</td>
<td></td>
<td></td>
<td align="center">1.00</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TC/AT</td>
<td align="center">789 (34.3)</td>
<td align="center">104 (36.8)</td>
<td align="center">323 (33.6)</td>
<td align="center">534 (33.1)</td>
<td align="center">1.06</td>
<td align="center">0.84 to 1.35</td>
<td></td>
<td align="center">0.94</td>
<td align="center">0.83 to 1.07</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">TT/AA</td>
<td align="center">141 (6.1)</td>
<td align="center">12 (4.2)</td>
<td align="center">48 (5.0)</td>
<td align="center">80 (4.9)</td>
<td align="center">0.74</td>
<td align="center">0.42 to 1.32</td>
<td></td>
<td align="center">0.87</td>
<td align="center">0.67 to 1.14</td>
<td></td>
<td></td>
</tr>
<tr><td align="center">Per-allele</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td align="center">0.97</td>
<td align="center">0.80 to 1.17</td>
<td align="center">0.73</td>
<td align="center">0.94</td>
<td align="center">0.85 to 1.03</td>
<td align="center">0.20</td>
<td align="center">0.77</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p><italic>P</italic>
-het, Heterogeneity <italic>P</italic>
-value; ER-, estrogen receptor negative; ER+, estrogen receptor positive</p>
</table-wrap-foot>
</table-wrap>
</sec>
<sec><title>Associations with PR status - BRCA1 mutation carriers</title>
<p>The general pattern of associations with PR-positive and PR-negative breast cancer for <italic>BRCA1 </italic>
mutation carriers (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>
, Table S3) was similar to that seen for ER status. Significant differences in the associations between PR-positive and PR-negative breast cancer were observed for three SNPs. The minor allele of <italic>FGFR2 </italic>
SNP rs2981582 was associated with a significantly higher risk for PR-positive breast cancer for <italic>BRCA1 </italic>
mutation carriers (per-allele HR for PR-positive = 1.29, 95% CI: 1.10 to 1.51, HR for PR-negative = 0.93, 95% CI: 0.87 to 1.00, P-heterogeneity = 7 × 10<sup>-4</sup>
). Allele "A" of SNP rs13387042 at 2q35 was associated with a significantly higher risk of PR-positive breast cancer for <italic>BRCA1 </italic>
mutation carriers (HR for PR-positive breast cancer = 1.16, 95% CI: 1.01 to 1.33; HR for PR-negative = 0.97, 95% CI: 0.91 to 1.04, <italic>P</italic>
-heterogeneity = 0.034). Although the <italic>RAD51L1 </italic>
SNP showed no differential associations with ER-status, there was evidence that the minor allele of this SNP was associated with a lower risk of PR-positive breast cancer (HR for PR-positive = 0.79, 95% CI: 0.61 to 0.95; HR for PR-negative = 1.02, 95% CI: 0.94 to 1.11; <italic>P</italic>
-heterogeneity = 0.027). The only SNPs associated with risk for PR-negative breast cancer were SNPs at 6q25.1 (per-allele HR = 1.19, 95% CI: 1.11 to 1.27, <italic>P</italic>
-trend = 3.7 × 10<sup>-7</sup>
), and in <italic>LSP1 </italic>
(per-allele HR = 1.09, 95% CI: 1.01 to 1.16, <italic>P</italic>
-trend = 0.017), but these were not significantly different from the associations with PR-positive breast cancer for <italic>BRCA1 </italic>
mutation carriers.</p>
</sec>
<sec><title>Associations with PR status - BRCA2 mutation carriers</title>
<p>Only two SNPs demonstrated significant differences in the associations with PR-positive and PR-negative breast cancer for <italic>BRCA2 </italic>
mutation carriers (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>
, Table S4). SNP rs13387042 at 2q35 was associated with a higher risk of PR-positive breast cancer (per-allele HR for PR-positive = 1.14, 95% CI: 1.03 to 1.25; per-allele HR for PR-negative = 0.92, 95% CI: 0.81 to 1.04, <italic>P</italic>
-heterogeneity = 0.009). SNP rs10941679 at 5p12 was also associated with a higher risk of PR-positive breast cancer for <italic>BRCA2 </italic>
mutation carriers (per-allele HR for PR-positive = 1.15. 95% CI: 1.03 to 1.27, HR for PR-negative = 0.94, 95% CI: 0.81 to 1.09, <italic>P</italic>
-heterogeneity = 0.028). SNPs near or at <italic>FGFR2, TOX3/TNRC9, LSP1 </italic>
were associated with both PR-negative and PR-positive breast cancer, whereas the 1p11.2 SNP was associated with risk for PR-negative breast cancer. <italic>MAP3K1 </italic>
and <italic>SLC4A7/NEK10 </italic>
were associated only with risk of PR-positive breast cancer among <italic>BRCA2 </italic>
mutation carriers.</p>
</sec>
<sec><title>Absolute risks of developing ER-positive and ER-negative breast cancer by SNP profile</title>
<p>Using the estimated HRs for ER-positive and ER-negative breast cancer for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers, we computed the predicted absolute risk of developing ER-negative and ER-positive breast cancer at various percentiles of the combined SNP distribution. The SNP profile distribution is different for each disease subtype and mutation. We note that SNPs for which the per-allele HR estimates are close to 1.0 contribute little to the predicted ER-specific risks. Figure <xref ref-type="fig" rid="F1">1</xref>
shows the predicted risks of developing ER-negative and ER-positive breast cancer for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers at the 5<sup>th</sup>
, 50<sup>th </sup>
and 95<sup>th </sup>
percentiles of the empirical risk distribution of the combined SNP profile. A <italic>BRCA1 </italic>
mutation carrier at the 5<sup>th </sup>
percentile of the SNP profile distribution would be at 43% risk of developing ER-negative breast cancer by age 80 compared with 60% for <italic>BRCA1 </italic>
mutation carriers at the 95<sup>th </sup>
percentile of the risk distribution. The risks of developing ER-positive breast cancer would be 18% and 46% by age 80 at the 5<sup>th </sup>
and 95<sup>th </sup>
percentiles of the ER-positive breast cancer risk distribution. <italic>BRCA2 </italic>
mutation carriers at the 5<sup>th </sup>
percentile of the ER-negative breast cancer risk distribution are predicted to have a 22% risk of developing ER-negative breast cancer by age 80 compared with 39% for the 95<sup>th </sup>
percentile of the risk distribution. The risks of developing ER-positive breast cancer by age 80 for <italic>BRCA2 </italic>
carriers varied from 33% to 70% at the 5<sup>th </sup>
and 95<sup>th </sup>
percentiles of the ER-positive risk distribution respectively.</p>
<fig id="F1" position="float"><label>Figure 1</label>
<caption><p><bold>Predicted risks of developing ER-negative and ER-positive breast cancer based on SNP profiles</bold>
. Solid lines depict the median risks and dotted lines the risks at the 5<sup>th </sup>
and 95<sup>th </sup>
percentiles of the risk distribution. The absolute risk differences between individuals at the extremes of the risk distributions are greater for ER-positive breast cancer.</p>
</caption>
<graphic xlink:href="bcr3052-1"></graphic>
</fig>
</sec>
</sec>
<sec><title>Discussion</title>
<p>This is the first report to investigate the associations between 12 common breast cancer susceptibility alleles and ER and PR status of breast tumours in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers. The analysis was made possible by the availability of a large, combined dataset with genotype and tumour pathology information in mutation carriers collated through the CIMBA consortium.</p>
<p>The majority of the SNPs examined demonstrated stronger associations with ER-positive breast cancer for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers (Figure <xref ref-type="fig" rid="F2">2</xref>
). Only rs2046210 on 6q25.1 exhibited stronger evidence for ER-negative disease. Among <italic>BRCA1 </italic>
mutation carriers, the most marked difference was for SNP rs2981582 in <italic>FGFR2</italic>
, which was strongly associated with ER-positive breast cancer and exhibited no evidence of an association with ER-negative breast cancer (<italic>P </italic>
= 6.5 × 10<sup>-6</sup>
). Previous analyses of this polymorphism in mutation carriers failed to find an association with the overall risk of breast cancer for <italic>BRCA1 </italic>
mutation carriers, but found an association with risk for <italic>BRCA2 </italic>
mutation carriers [<xref ref-type="bibr" rid="B29">29</xref>
,<xref ref-type="bibr" rid="B31">31</xref>
]. Our results suggest that rs2981582 in <italic>FGFR2 </italic>
also modifies ER-positive breast cancer risk for <italic>BRCA1 </italic>
mutation carriers to a similar relative extent as in <italic>BRCA2 </italic>
mutation carriers and ER-positive disease in the general population [<xref ref-type="bibr" rid="B27">27</xref>
,<xref ref-type="bibr" rid="B32">32</xref>
]. Similar patterns were observed for SNPs rs3803662 in <italic>TOX3/TNRC9 </italic>
and rs4973768 in <italic>SLC4A7/NEK10 </italic>
in which the associations were predominantly with ER-positive breast cancer for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers, in line with results from studies of breast cancer in the general population [<xref ref-type="bibr" rid="B18">18</xref>
,<xref ref-type="bibr" rid="B21">21</xref>
,<xref ref-type="bibr" rid="B27">27</xref>
]. The HR estimates for ER-positive breast cancer in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers for these SNPs were very similar.</p>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p><bold>Summary of per-allele HR estimates for ER-positive and ER-negative breast cancer for mutation carriers</bold>
. The patterns of per-allele HR estimates (taken from Tables 2 and 3) suggest that the breast cancer subtype specific associations are similar between <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers.</p>
</caption>
<graphic xlink:href="bcr3052-2"></graphic>
</fig>
<p>Among the 12 SNPs investigated in this report, SNP rs2046210 at 6q25.1 exhibited the strongest association with the risk of breast cancer for <italic>BRCA1 </italic>
mutation carriers in previous analyses, and was not associated with risk for <italic>BRCA2 </italic>
mutation carriers [<xref ref-type="bibr" rid="B28">28</xref>
]. The current results suggest that this was mainly driven by an association with ER-negative breast cancer risk. This observation is again consistent with the effects seen in population-based studies, in which the relative risk is higher for ER-negative than ER-positive disease [<xref ref-type="bibr" rid="B42">42</xref>
,<xref ref-type="bibr" rid="B43">43</xref>
] (Alison Dunning, personal communication). There was some evidence that the 6q25.1 SNP is also associated with ER-negative disease cancer subtype in <italic>BRCA2 </italic>
mutation carriers, although the estimates for ER-negative breast cancer in <italic>BRCA2 </italic>
mutation carriers are imprecise due to the relatively small sample size. In addition to the 12 loci investigated in this report, a recently identified locus at 19p13 also appears to be predominantly associated with ER-negative breast cancer [<xref ref-type="bibr" rid="B44">44</xref>
].</p>
<p>The patterns of association between the SNPs and PR tumour status were similar to those observed for ER, which is not surprising given that ER and PR expression are highly correlated. There were, however, two notable exceptions. The 2q35 SNP rs13387042 demonstrated significantly stronger associations with PR-positive than PR-negative breast cancer for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers (<italic>P </italic>
= 0.034 and <italic>P </italic>
= 0.0086, for PR-positive for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
respectively), suggesting this SNP may be more relevant for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
tumours expressing PR. However, a population-based study has found this SNP is also associated with PR-negative breast cancer [<xref ref-type="bibr" rid="B45">45</xref>
]. Furthermore, the <italic>RAD51L1 </italic>
locus was associated with PR-positive breast cancer for <italic>BRCA1 </italic>
mutation carriers and the magnitude of the association was similar to that observed in the general population [<xref ref-type="bibr" rid="B23">23</xref>
] (A.B. Spurdle, personal communication).</p>
<p>Previous studies demonstrated that SNPs, which are associated with ER-positive breast cancer in the general population, tend to be associated with the breast cancer risk for <italic>BRCA2 </italic>
mutation carriers and SNPs, which are associated with ER-negative breast cancer in the general population, tend to be associated with the breast cancer risk for <italic>BRCA1 </italic>
mutation carriers [<xref ref-type="bibr" rid="B27">27</xref>
,<xref ref-type="bibr" rid="B31">31</xref>
,<xref ref-type="bibr" rid="B44">44</xref>
-<xref ref-type="bibr" rid="B46">46</xref>
]. The current results demonstrate that despite lack of an association between a SNP and the overall breast cancer risk for <italic>BRCA1 </italic>
or <italic>BRCA2 </italic>
mutation carriers, residual associations exist with specific disease subtypes. Figure <xref ref-type="fig" rid="F2">2</xref>
summarises the association patterns in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers. The HR estimates for ER-positive and ER-negative breast cancer among <italic>BRCA1 </italic>
mutation carriers appear to be different (intraclass correlation coefficient (ICC) approximately 0), as are the HR estimates for ER-positive and ER-negative breast cancer among <italic>BRCA2 </italic>
mutation carriers (ICC = 0.13). On the other hand the HR estimates for ER-positive breast cancer among <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers appear to be more similar (ICC = 0.65). There is, however, little correlation in the HR estimates for ER-negative breast cancer among <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers (ICC = 0.05). However, SNP 6q25.1, which is mainly associated with ER-negative disease in <italic>BRCA1 </italic>
mutation carriers, is estimated to confer similar HRs for ER-negative breast cancer for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers. These associations are mainly in the same direction and of similar magnitude to those observed with breast cancer in the general population stratified by ER expression status. Taken together, these findings are consistent with a model in which these SNPs and <italic>BRCA1 </italic>
or <italic>BRCA2 </italic>
mutations combine multiplicatively on the risk for ER-positive or ER-negative breast cancer [<xref ref-type="bibr" rid="B47">47</xref>
]. Hence, the apparent differences in the strength of the SNP associations by <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation status can be explained once tumour subtype is taken into account.</p>
<p>The major strength of the current study is the large sample of <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers with SNP and tumour marker information. Despite the large sample size, ER and PR marker information was only available for approximately 30% of the mutation carriers that had been diagnosed with breast cancer. The sample sizes for tumour subtypes, while still large, were, therefore, much smaller than were available for analyses of breast cancer risk overall, particularly for ER-positive breast cancer in <italic>BRCA1 </italic>
carriers and ER-negative breast cancer in <italic>BRCA2 </italic>
carriers. However, by analysing the data using a retrospective cohort approach and analysing the associations with ER-positive and ER-negative disease simultaneously we were able to include all mutation carriers in the analysis, including affected individuals with missing ER status, thus maximizing the available information. Ongoing efforts by CIMBA aim to increase the proportion of mutation carriers diagnosed with breast cancer who also have available tumour pathology information. This will enable us to assess the associations with breast cancer subtypes with greater precision.</p>
<p>The majority of the mutation carriers in CIMBA are identified through clinical genetics centers and, therefore, the source of information or definition of tumour marker status could vary across studies. This heterogeneity in classification may attenuate some of the differences by tumour type. For example, most commonly, a cut-off of 10% of cells staining was taken to denote positivity for ER and PR by the centers without further information on intensity or proportion of positive tumour nuclei and this was used for all our analyses; however, in centers that use the Allred score, a value of > 2 denoted positivity, which may reflect as few as 1% of cells staining. In fact, recent recommendations suggest that ER and PgR assays be considered positive, for therapeutic purposes, if there are at least 1% positive tumour nuclei [<xref ref-type="bibr" rid="B48">48</xref>
], but these data were not available for the majority of carriers in our samples to enable reclassification. It has been shown, however, that ER is almost always diffusely positive or completely negative (that is, it shows a bimodal staining pattern) with few cases falling between these extremes [<xref ref-type="bibr" rid="B49">49</xref>
]. Given the small number of tumours likely to fall into the1 to 9% of cells staining category, the impact of changing the cutoff to 1% on our results would be limited. Furthermore, there was no evidence of variation in the distributions of ER or PR status across the studies separately for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
tumours (Mavaddat N, Antoniou AC, personal communication, manuscript in preparation) and all analyses were stratified by country. Finally, the clear differences observed for some SNPs (most notably for <italic>FGFR2 </italic>
rs2981582, where the association was limited to ER-positive disease) suggest that the effect of misclassification in tumour subtype on the SNP associations is likely to have been small.</p>
<p><italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
tumours have also been found to differ in terms of other tumour characteristics compared to breast cancers in the general population. For example, tumours in mutation carriers are more likely to be of higher grade in comparison to breast cancers in the general population. The distribution of grade has been found to vary between ER-positive and ER-negative tumours in both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers (Mavaddat N, Antoniou AC, personal communication, manuscript in preparation). Although the number of carriers with information on grade, ER status and SNPs was too small to permit combined analysis, our results are unlikely to have been influenced after adjusting for tumour grade. Case-only analysis to test for differences in associations between the SNPs and tumour grade (using ordinal logistic regression) revealed no significant associations between any of the SNPs and grade for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers (<italic>P </italic>
> 0.05 for all tests, results not shown).</p>
<p>The analysis was performed within a retrospective cohort approach, by extending the retrospective likelihood approach described previously [<xref ref-type="bibr" rid="B36">36</xref>
] to model the simultaneous effects on different breast cancer subtypes defined by ER/PR. Under this approach the associations were estimated simultaneously for the tumour subtypes under investigation. This method depends on the assumption that ascertainment of mutation carriers does not depend on tumour subtypes. This is a reasonable assumption since more than 90% of mutation carriers in our sample were recruited prior to 2007, when it was uncommon to use tumour pathology in selecting individuals for <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation screening. Furthermore, the results were virtually identical in a case only, logistic regression analysis for testing for differences in the associations with tumour subtypes which included only individuals with known tumour characteristics (results not shown).</p>
<p>The average risks of developing ER-positive and ER-negative breast cancer in both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers are substantially higher compared to the general population [<xref ref-type="bibr" rid="B38">38</xref>
]. Therefore, in combination, these SNPs lead to much bigger differences in the absolute risk of developing the disease subtypes between the extremes of the combined SNP genotype distributions [<xref ref-type="bibr" rid="B50">50</xref>
]. Based on the SNP profiles investigated in this report, the absolute risk difference between mutation carriers at the top 5% of the risk distribution compared to the bottom 5% is much greater for ER-positive breast cancer than for ER-negative breast cancer for both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
(Figure <xref ref-type="fig" rid="F1">1</xref>
). Recent GWAS have identified several other common breast cancer susceptibility variants which have not been investigated in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers yet [<xref ref-type="bibr" rid="B24">24</xref>
,<xref ref-type="bibr" rid="B51">51</xref>
]. Moreover, ongoing GWAS in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers [<xref ref-type="bibr" rid="B44">44</xref>
,<xref ref-type="bibr" rid="B52">52</xref>
] may also identify further modifiers of breast cancer risk for mutation carriers. It will be important to investigate the associations of these variants with different disease subtypes in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers. Currently, it is unusual for the risks of different disease subtypes to be taken into account in the genetic counseling process. However, as more risk modifying variants are identified in the future, provided these have different associations with different disease subtypes in mutation carriers and confer relative risks which are greater (or smaller) than 1, having precise breast cancer subtype risks may be useful for the planning of the clinical management of both <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers. For example, knowing that a female <italic>BRCA1 </italic>
mutation carrier was primarily at risk of ER-positive breast cancer based on her associated SNP profile (rather than ER-negative breast cancer, as is the case for the majority of cases) might potentially influence the choice of clinical management by screening, chemoprevention or prophylactic surgery.</p>
</sec>
<sec><title>Conclusions</title>
<p>In summary, in this report we investigated the associations of common breast cancer polymorphisms with ER and PR status. Our results indicate there are differential associations between these SNPs and the risk of developing ER-positive or ER-negative breast cancer in <italic>BRCA1 </italic>
and <italic>BRCA2 </italic>
mutation carriers that mirror similar differences seen in the general population. The findings add to our understanding of the biology of tumour development in mutation carriers and as more risk variants are identified in the future they may improve clinical management of these individuals.</p>
</sec>
<sec><title>Abbreviations</title>
<p>CIMBA: Consortium of Investigators of Modifiers of BRCA1/2; ER: estrogen receptor; GWAS: genome-wide association studies; HR: hazard ratio; PR: progesterone receptor; SNPs: single nucleotide polymorphisms.</p>
</sec>
<sec><title>Competing interests</title>
<p>The authors declare that they have no competing interests.</p>
</sec>
<sec><title>Authors' contributions</title>
<p>AMM, ILA, ACA drafted the initial manuscript. ACA developed the analytical methods and performed the statistical analysis. AMM, ACA, ILA, FJC, DB, SMD, DE, HN, SJR, MR, MS, ABS and BW are members of the CIMBA pathology working group and participated in the design of the study. LM and DB are the CIMBA database managers. AL wrote computer programs for the analysis. SH and OMS reviewed, recoded and classified the BRCA1 and BRCA2 mutations in CIMBA. GCT initiated and coordinated CIMBA. DFE participated in the study design and advised on the statistical analysis. RJ, TvOH, FCNi, BE, AO, IMR, MD, JG, MP, JB, PP, SM, BP, DZ, EC, BB, AV, BP, LP, LO, AS, LB, PR, UH, MV, HEJMH, JW, EBGG, MRN, MK, CS, MMATL, RBvdL, TvO, MR, DF, JLJ, DGE, FL, RE, LI, JA, RD, JC, AD, HD, HG, JE, CH, JB, LES, E McC, AM, SP, AG, RKS, KR, CE, AM, IR, NA, DN, CS, HD, DG, KK, SPA, RVM, IS, BF, WH, DS, HG, VCM, FCFC, SM, ML, NBK, AH, PB, DM, JPF, IM, PP, IC, ML, CK, ML, NS, DSL, CI, TC, MH, TH, KA,IB, CL, RBB, PS, MD, JS, MM, ST, EDA, SF, MY, TR, OO, JNW, HTL, PAG, GET, XW, ZF, VSP, NML, CS, KO, RS, MG, JB, NK, CFS, MKT, DGK, AFR, PLM, MHG, EI, FPO, HO, GG, AET, AMG, MT, TAK, UBJ, ABS, MAC, MS, KH, AvW, BA, MSA, PK, YCD, SLN, MB, PDPP, KBM, KLN, BYK, JG, EMJ, MJD, SMB, MCS, JLH, MBT, WC, AFM and DG acquired phenotypic data and DNA samples or performed SNP genotyping. All authors read and approved the final manuscript.</p>
</sec>
<sec sec-type="supplementary-material"><title>Supplementary Material</title>
<supplementary-material content-type="local-data" id="S1"><caption><title>Additional file 1</title>
<p><bold>Supplementary Tables</bold>
. Supplementary Table 1: List of local ethics committees that approved studies. Supplementary Table 2: Methods and thresholds used to define the final marker variables. Supplementary Table 3: Per-allele hazard ratio estimates by progesterone receptor status for <italic>BRCA1 </italic>
mutation carriers. Supplementary Table 4: Per-allele hazard ratio estimates by progesterone receptor status for <italic>BRCA2 </italic>
mutation carriers.</p>
</caption>
<media xlink:href="bcr3052-S1.DOC" mimetype="application" mime-subtype="msword"><caption><p>Click here for file</p>
</caption>
</media>
</supplementary-material>
</sec>
</body>
<back><sec><title>Acknowledgements</title>
<p>This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175). ACA is a CR-UK Senior Cancer Research Fellow, DFE is CR-UK Principal Research Fellow.</p>
<sec><title>Study specific acknowledgments</title>
<sec><title>Breast Cancer Family Registry (BCFR)</title>
<p>This work was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (formerly the Northern California Cancer Center) (U01 CA69417), University of Melbourne (U01 CA69638), and Research Triangle Institute Informatics Support Center (RFP No. N02PC45022-46). Samples from the FCCC, HCI, and CPIC were processed and distributed by the Coriell institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.</p>
</sec>
<sec><title>The Baltic Familial Breast and Ovarian Cancer Consortium (BFBOCC Latvia and Lithuania)</title>
<p>Lithuania: This work is supported by the Research Council of Lithuania grant LIG-19/2010 to Ramunas Janavicius. Latvia: We acknowledge Genome Database of Latvian Population, Latvian Biomedical Research and Study Center for providing data and DNA samples. This work is supported by Liepaja's municipal council to Laima Tihomirova (Latvian Biomedical Research and Study Centre).</p>
</sec>
<sec><title>Copenhagen Breast Cancer Study (CBCS)</title>
<p>We thank the NEYE Foundation for financial support</p>
<p>The Deutsches Krebsforschungszentrum (DKFZ) study</p>
<p>The study was supported by the DKFZ.</p>
<p>The CONSIT TEAM is supported by grants from Associazione Italiana per la Ricerca sul Cancro (4017) and by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumouri, according to Italian laws (INT-Institutional strategic projects "5 × 1000") to PP and grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumours"), Ministero della Salute (Extraordinary National Cancer Program 2006 "Alleanza contro il Cancro", and "Progetto Tumouri Femminili") and Ministero dell'Universita' e Ricerca (RBLAO3-BETH) to PR. CONSIT TEAM acknowledges the contribution of Gaia Roversi, Carla B. Ripamonti, Marilena Morganti and Marco Pierotti of the of the Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy; Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy and Liliana Varesco of the Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.</p>
</sec>
<sec><title>Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE)</title>
<p>EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Steve Ellis, Elena Fineberg, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: T. Rogers,. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow. Leicestershire Clinical Genetics Service, Leicester. Yorkshire Regional Genetics Service, Leeds: Carol Chu, Julie Miller. Cheshire and Merseyside Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D'Mello are also supported by Cancer Research UK Grant C5047/A8385.</p>
</sec>
<sec><title>Fox Chase Cancer Center Study (FCCC)</title>
<p>Fox Chase Cancer Center Biosample Repository: We acknowledge M. Pat Gilroy, Lesley Cruz, Diane Faison, Barbara Dettore, Mary Donovan, and Meghan Butler for their help collecting patient data and samples. University of Kansas Medical Center (KUMC):</p>
<p>A.K.G. was funded by U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund. The author acknowledges support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor.</p>
</sec>
<sec><title>Georgetown University</title>
<p>Work is supported by the Familial Cancer Registry (CI) and the Tissue Culture Shared Registry at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C) (CI), and Swing Fore the Cure (CI).</p>
</sec>
<sec><title>The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC)</title>
<p>GC-HBOC is supported by a grant of the German Cancer Aid (grant 109076), the Centre of Molecular Medicine Cologne (CMMC).</p>
</sec>
<sec><title>Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO) study: Cancer Genetics Network "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer, France</title>
<p>The study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association "Le cancer du sein, parlons-en!" Award. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, et Equipe «Génétique du cancer du sein», Centre de Recherche en Cancérologie de Lyon: Laure Barjhoux, Carole Verny-Pierre, Sophie Giraud, and Service de Génétique Oncologique, Institut Curie, Paris: Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Muriel Belotti, Carole Tirapo, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Véronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre François Baclesse, Caen. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, François Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis. Hôpital René Huguenin/Institut Curie, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg. Institut Bergonié, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon. CHU de Dijon: Fanny Coron, Laurence Faivre. CHU de St-Etienne: Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. CHU de Nantes: Capucine Delnatte. CHU Bretonneau, Tours. Creighton University, Omaha, USA: Henry T.Lynch, Carrie L.Snyder.</p>
</sec>
<sec><title>The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)</title>
<p>HEBON Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: FBL Hogervorst, S Verhoef, M Verheus, LJ van 't Veer, FE van Leeuwen; Erasmus Medical Center, Rotterdam, NL: M Collée, AMW van den Ouweland, A Jager, MJ Hooning; Leiden University Medical Center, NL, Leiden: CJ van Asperen, JT Wijnen, MP Vreeswijk, RA Tollenaar, P Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: MJ Ligtenberg, N Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: MG Ausems; Amsterdam Medical Center, NL: CM Aalfs; VU University Medical Center, Amsterdam, NL: JJP Gille, Q Waisfisz, HEJ Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: EB Gomez-Garcia, CE van Roozendaal, Marinus J Blok, B Caanen; University Medical Center Groningen University, NL: JC Oosterwijk, AH van der Hout, MJ Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: HF Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756 and the ZonMW grant 91109024.</p>
</sec>
<sec><title>Helsinki Breast Cancer Study (HEBCS)</title>
<p>HEBCS acknowledge Drs. Kirsimari Aaltonen, Carl Blomqvist and Päivi Heikkilä and research nurse Irja Erkkilä for their help with the patient data and samples. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.</p>
</sec>
<sec><title>Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT BRCAs)</title>
<p>We would like to thank Martine Tranchant for skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and by the Canadian Breast Cancer Research Alliance-grant #019511.</p>
</sec>
<sec><title>ILUH</title>
<p>The ILUH group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund.</p>
</sec>
<sec><title>Istituto Oncologico Veneto Hereditary Breast and Ovarian Cancer Study (IOVHBOCS)</title>
<p>This study was supported by "Ministero della Salute" ("Progetto Tumouri Femminili and grant numbers RFPS 2006-5-341353, ACC2/R6.9")</p>
</sec>
<sec><title>Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab)</title>
<p>We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. ABS and GCT are NHMRC Fellows.</p>
</sec>
<sec><title>Mayo Clinic Study</title>
<p>The MAYO study was supported by NIH grants CA116167, CA128978, a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and awards from the Komen Foundation for the Cure and the Breast Cancer Research Foundation.</p>
</sec>
<sec><title>Memorial Sloan-Kettering Cancer Center (MSKCC)</title>
<p>The study is supported by grant from the Breast Cancer Research Foundation, Starr Cancer Consortium, Norman and Carol Stone Genetic Research Fund, The Robert and Kate Niehaus Clinical Genetics Initiative at MSKCC</p>
</sec>
<sec><title>National Cancer Institute study (NCI)</title>
<p>The research of Drs. PL Mai and MH Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD.</p>
</sec>
<sec><title>N.N. Petrov Institute of Oncology</title>
<p>This work has been supported by the Russian Federation for Basic Research (grants 10-04-92601, 10-04-92110, 11-04-00227), the Federal Agency for Science and Innovations (contract 02.740.11.0780), the Commission of the European Communities (grant PITN-GA-2009-238132) and through a Royal Society International Joint grant (JP090615).</p>
</sec>
<sec><title>Ontario Cancer Genetics Network (OCGN)</title>
<p>We wish to thank Mona Gill, Lucine Collins, Nalan Gokgoz, Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study.</p>
</sec>
<sec><title>The Ohio State University Comprehensive Cancer Center (OSU-CCG)</title>
<p>This work was supported by the Ohio State University Comprehensive Cancer Center. We thank Kevin Sweet and Leigha Senter for accrual of study participants and data management. The Human Genetics Sample bank prepared DNA samples and the OSU Nucleic Acids Shared Resource assisted with genotyping.</p>
</sec>
<sec><title>Swedish BRCA1 and BRCA2 study (SWE-BRCA)</title>
<p>SWE-BRCA collaborators: Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Sigrun Liedgren, Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Katja Harbst, Lund University Hospital; Annika Lindblom, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin and Monica Emanuelsson, Umeå University Hospital; Hans Ehrencrona, Richard Rosenquist and Niklas Dahl, Uppsala University Hospital.</p>
</sec>
<sec><title>University California San Francisco (UCSF)</title>
<p>The study received funding from the NIH, NCI Bay Area Breast Cancer SPORE (P50 CA 058207) and the Avon Foundation. We acknowledge support from the UCSF Helen Diller Family Comprehensive Cancer Center</p>
</sec>
<sec><title>UK and Gilda Radner Familial Ovarian Cancer Registries (UKGRFOCR)</title>
<p>UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Simon Gayther, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. We'd like to acknowledge the Roswell Park Alliance Foundation for their continued support of the Gilda Radner Ovarian Family Cancer Registry. GRFOCR would like to acknowledge Lara Sucheston (Department of Cancer Prevention and Control) and Kunle Odunsi (Departments Gynecologic Oncology and Immunology).</p>
</sec>
<sec><title>University of Pennsylvania (UPENN)</title>
<p>Work is supported by grants from the Breast Cancer Research Foundation (to KLN), MacDonald Family Foundation (SMD) and Komen Foundation (SMD)</p>
</sec>
</sec>
</sec>
<ref-list><ref id="B1"><mixed-citation publication-type="journal"><name><surname>Ford</surname>
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