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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics</title><author><name sortKey="Garcia Closas, Montserrat" sort="Garcia Closas, Montserrat" uniqKey="Garcia Closas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></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="aff3"><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pooley, Karen" sort="Pooley, Karen" uniqKey="Pooley K" first="Karen" last="Pooley">Karen Pooley</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Morrison, Jonathan" sort="Morrison, Jonathan" uniqKey="Morrison J" first="Jonathan" last="Morrison">Jonathan Morrison</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Richesson, Douglas A" sort="Richesson, Douglas A" uniqKey="Richesson D" first="Douglas A." last="Richesson">Douglas A. Richesson</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Clinical Biochemistry, Herlev and Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>Department of Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G." last="Nordestgaard">B Rge G. Nordestgaard</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Clinical Biochemistry, Herlev and Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Axelsson, Christen K" sort="Axelsson, Christen K" uniqKey="Axelsson C" first="Christen K." last="Axelsson">Christen K. Axelsson</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Arias, Jose I" sort="Arias, Jose I" uniqKey="Arias J" first="Jose I." last="Arias">Jose I. Arias</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Monte Naranco Hospital, Oviedo, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ribas, Gloria" sort="Ribas, Gloria" uniqKey="Ribas G" first="Gloria" last="Ribas">Gloria Ribas</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gonzalez Neira, Anna" sort="Gonzalez Neira, Anna" uniqKey="Gonzalez Neira A" first="Anna" last="González-Neira">Anna González-Neira</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></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="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zamora, Pilar" sort="Zamora, Pilar" uniqKey="Zamora P" first="Pilar" last="Zamora">Pilar Zamora</name><affiliation><nlm:aff id="aff10"><addr-line>La Paz Hospital, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="aff11"><addr-line>Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Justenhoven, Christina" sort="Justenhoven, Christina" uniqKey="Justenhoven C" first="Christina" last="Justenhoven">Christina Justenhoven</name><affiliation><nlm:aff id="aff11"><addr-line>Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany</addr-line></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="aff12"><addr-line>Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ko, Yon Dschun" sort="Ko, Yon Dschun" uniqKey="Ko Y" first="Yon-Dschun" last="Ko">Yon-Dschun Ko</name><affiliation><nlm:aff id="aff13"><addr-line>Evangelische Kliniken Bonn gGmhH Johanniter Krankenhaus, Bonn, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bruening, Thomas" sort="Bruening, Thomas" uniqKey="Bruening T" first="Thomas" last="Bruening">Thomas Bruening</name><affiliation><nlm:aff id="aff14"><addr-line>Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin, Ruhr University Bochum, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haas, Susanne" sort="Haas, Susanne" uniqKey="Haas S" first="Susanne" last="Haas">Susanne Haas</name><affiliation><nlm:aff id="aff15"><addr-line>Institute für Pathology, University Bonn, Bonn, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dork, Thilo" sort="Dork, Thilo" uniqKey="Dork T" first="Thilo" last="Dörk">Thilo Dörk</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schurmann, Peter" sort="Schurmann, Peter" uniqKey="Schurmann P" first="Peter" last="Schürmann">Peter Schürmann</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hillemanns, Peter" sort="Hillemanns, Peter" uniqKey="Hillemanns P" first="Peter" last="Hillemanns">Peter Hillemanns</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bogdanova, Natalia" sort="Bogdanova, Natalia" uniqKey="Bogdanova N" first="Natalia" last="Bogdanova">Natalia Bogdanova</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bremer, Michael" sort="Bremer, Michael" uniqKey="Bremer M" first="Michael" last="Bremer">Michael Bremer</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Karstens, Johann Hinrich" sort="Karstens, Johann Hinrich" uniqKey="Karstens J" first="Johann Hinrich" last="Karstens">Johann Hinrich Karstens</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fagerholm, Rainer" sort="Fagerholm, Rainer" uniqKey="Fagerholm R" first="Rainer" last="Fagerholm">Rainer Fagerholm</name><affiliation><nlm:aff id="aff3"><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aaltonen, Kirsimari" sort="Aaltonen, Kirsimari" uniqKey="Aaltonen K" first="Kirsimari" last="Aaltonen">Kirsimari Aaltonen</name><affiliation><nlm:aff id="aff3"><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><addr-line>Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></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="aff19"><addr-line>Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Von Smitten, Karl" sort="Von Smitten, Karl" uniqKey="Von Smitten K" first="Karl" last="Von Smitten">Karl Von Smitten</name><affiliation><nlm:aff id="aff20"><addr-line>Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Blomqvist, Carl" sort="Blomqvist, Carl" uniqKey="Blomqvist C" first="Carl" last="Blomqvist">Carl Blomqvist</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="aff21"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><addr-line>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uusitupa, Matti" sort="Uusitupa, Matti" uniqKey="Uusitupa M" first="Matti" last="Uusitupa">Matti Uusitupa</name><affiliation><nlm:aff id="aff23"><addr-line>Department of Public Health and Clinical Nutrition, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eskelinen, Matti" sort="Eskelinen, Matti" uniqKey="Eskelinen M" first="Matti" last="Eskelinen">Matti Eskelinen</name><affiliation><nlm:aff id="aff24"><addr-line>Department of Surgery, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tengstrom, Maria" sort="Tengstrom, Maria" uniqKey="Tengstrom M" first="Maria" last="Tengström">Maria Tengström</name><affiliation><nlm:aff id="aff25"><addr-line>Department of Oncology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><addr-line>Department of Oncology, Vaasa Central Hospital, Vaasa, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kosma, Veli Matti" sort="Kosma, Veli Matti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><nlm:aff id="aff21"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><addr-line>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kataja, Vesa" sort="Kataja, Vesa" uniqKey="Kataja V" first="Vesa" last="Kataja">Vesa Kataja</name><affiliation><nlm:aff id="aff25"><addr-line>Department of Oncology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><addr-line>Department of Oncology, Vaasa Central Hospital, Vaasa, Finland</addr-line></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="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></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="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beesley, Jonathan" sort="Beesley, Jonathan" uniqKey="Beesley J" first="Jonathan" last="Beesley">Jonathan Beesley</name><affiliation><nlm:aff id="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chen, Xiaoqing" sort="Chen, Xiaoqing" uniqKey="Chen X" first="Xiaoqing" last="Chen">Xiaoqing Chen</name><affiliation><nlm:aff id="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Devilee, Peter" sort="Devilee, Peter" uniqKey="Devilee P" first="Peter" last="Devilee">Peter Devilee</name><affiliation><nlm:aff id="aff29"><addr-line>Departments of Human Genetics and Pathology, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Asperen, Christi J" sort="Van Asperen, Christi J" uniqKey="Van Asperen C" first="Christi J." last="Van Asperen">Christi J. Van Asperen</name><affiliation><nlm:aff id="aff30"><addr-line>Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jacobi, Catharina E" sort="Jacobi, Catharina E" uniqKey="Jacobi C" first="Catharina E." last="Jacobi">Catharina E. Jacobi</name><affiliation><nlm:aff id="aff31"><addr-line>Department of Medical Decision Making, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tollenaar, Rob A E M" sort="Tollenaar, Rob A E M" uniqKey="Tollenaar R" first="Rob A. E. M." last="Tollenaar">Rob A. E. M. Tollenaar</name><affiliation><nlm:aff id="aff32"><addr-line>Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huijts, Petra E A" sort="Huijts, Petra E A" uniqKey="Huijts P" first="Petra E. A." last="Huijts">Petra E. A. Huijts</name><affiliation><nlm:aff id="aff33"><addr-line>Department of Medical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Klijn, Jan G M" sort="Klijn, Jan G M" uniqKey="Klijn J" first="Jan G. M." last="Klijn">Jan G. M. Klijn</name><affiliation><nlm:aff id="aff33"><addr-line>Department of Medical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="aff34"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kropp, Silke" sort="Kropp, Silke" uniqKey="Kropp S" first="Silke" last="Kropp">Silke Kropp</name><affiliation><nlm:aff id="aff34"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Slanger, Tracy" sort="Slanger, Tracy" uniqKey="Slanger T" first="Tracy" last="Slanger">Tracy Slanger</name><affiliation><nlm:aff id="aff34"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flesch Janys, Dieter" sort="Flesch Janys, Dieter" uniqKey="Flesch Janys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="aff35"><addr-line>Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mutschelknauss, Elke" sort="Mutschelknauss, Elke" uniqKey="Mutschelknauss E" first="Elke" last="Mutschelknauss">Elke Mutschelknauss</name><affiliation><nlm:aff id="aff35"><addr-line>Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Salazar, Ramona" sort="Salazar, Ramona" uniqKey="Salazar R" first="Ramona" last="Salazar">Ramona Salazar</name><affiliation><nlm:aff id="aff36"><addr-line>Bioglobe GmbH, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang Gohrke, Shan" sort="Wang Gohrke, Shan" uniqKey="Wang Gohrke S" first="Shan" last="Wang-Gohrke">Shan Wang-Gohrke</name><affiliation><nlm:aff id="aff37"><addr-line>Molecular Biology Laboratory, Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus" sort="Couch, Fergus" uniqKey="Couch F" first="Fergus" last="Couch">Fergus Couch</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Goode, Ellen L" sort="Goode, Ellen L" uniqKey="Goode E" first="Ellen L." last="Goode">Ellen L. Goode</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E." last="Olson">Janet E. Olson</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vachon, Celine" sort="Vachon, Celine" uniqKey="Vachon C" first="Celine" last="Vachon">Celine Vachon</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fredericksen, Zachary S" sort="Fredericksen, Zachary S" uniqKey="Fredericksen Z" first="Zachary S." last="Fredericksen">Zachary S. Fredericksen</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff39"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><affiliation><nlm:aff id="aff39"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name><affiliation><nlm:aff id="aff39"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></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="aff40"><addr-line>Centre for MEGA Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="English, Dallas R" sort="English, Dallas R" uniqKey="English D" first="Dallas R." last="English">Dallas R. English</name><affiliation><nlm:aff id="aff40"><addr-line>Centre for MEGA Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></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="aff41"><addr-line>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Henderson, Brian E" sort="Henderson, Brian E" uniqKey="Henderson B" first="Brian E." last="Henderson">Brian E. Henderson</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kolonel, Laurence N" sort="Kolonel, Laurence N" uniqKey="Kolonel L" first="Laurence N." last="Kolonel">Laurence N. Kolonel</name><affiliation><nlm:aff id="aff43"><addr-line>Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Le Marchand, Loic" sort="Le Marchand, Loic" uniqKey="Le Marchand L" first="Loic" last="Le Marchand">Loic Le Marchand</name><affiliation><nlm:aff id="aff43"><addr-line>Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stram, Daniel O" sort="Stram, Daniel O" uniqKey="Stram D" first="Daniel O." last="Stram">Daniel O. Stram</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hunter, David J" sort="Hunter, David J" uniqKey="Hunter D" first="David J." last="Hunter">David J. Hunter</name><affiliation><nlm:aff id="aff45"><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hankinson, Susan E" sort="Hankinson, Susan E" uniqKey="Hankinson S" first="Susan E." last="Hankinson">Susan E. Hankinson</name><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, David G" sort="Cox, David G" uniqKey="Cox D" first="David G." last="Cox">David G. Cox</name><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff47"><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tamimi, Rulla" sort="Tamimi, Rulla" uniqKey="Tamimi R" first="Rulla" last="Tamimi">Rulla Tamimi</name><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kraft, Peter" sort="Kraft, Peter" uniqKey="Kraft P" first="Peter" last="Kraft">Peter Kraft</name><affiliation><nlm:aff id="aff47"><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sherman, Mark E" sort="Sherman, Mark E" uniqKey="Sherman M" first="Mark E." last="Sherman">Mark E. Sherman</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="aff48"><addr-line>Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lissowska, Jolanta" sort="Lissowska, Jolanta" uniqKey="Lissowska J" first="Jolanta" last="Lissowska">Jolanta Lissowska</name><affiliation><nlm:aff id="aff49"><addr-line>Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brinton, Louise A" sort="Brinton, Louise A" uniqKey="Brinton L" first="Louise A." last="Brinton">Louise A. Brinton</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peplonska, Beata" sort="Peplonska, Beata" uniqKey="Peplonska B" first="Beata" last="Peplonska">Beata Peplonska</name><affiliation><nlm:aff id="aff50"><addr-line>Nofer Institute of Occupational Medicine, Lodz, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Klijn, Jan G M" sort="Klijn, Jan G M" uniqKey="Klijn J" first="Jan G. M." last="Klijn">Jan G. M. Klijn</name><affiliation><nlm:aff id="aff51"><addr-line>Daniel den Hoed Cancer Center, Erasmus Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hooning, Maartje J" sort="Hooning, Maartje J" uniqKey="Hooning M" first="Maartje J." last="Hooning">Maartje J. Hooning</name><affiliation><nlm:aff id="aff51"><addr-line>Daniel den Hoed Cancer Center, Erasmus Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meijers Heijboer, Han" sort="Meijers Heijboer, Han" uniqKey="Meijers Heijboer H" first="Han" last="Meijers-Heijboer">Han Meijers-Heijboer</name><affiliation><nlm:aff id="aff52"><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Collee, J Margriet" sort="Collee, J Margriet" uniqKey="Collee J" first="J. Margriet" last="Collee">J. Margriet Collee</name><affiliation><nlm:aff id="aff52"><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Den Ouweland, Ans" sort="Van Den Ouweland, Ans" uniqKey="Van Den Ouweland A" first="Ans" last="Van Den Ouweland">Ans Van Den Ouweland</name><affiliation><nlm:aff id="aff52"><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="Andre G." last="Uitterlinden">Andre G. Uitterlinden</name><affiliation><nlm:aff id="aff53"><addr-line>Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name><affiliation><nlm:aff id="aff54"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lin, Low Yen" sort="Lin, Low Yen" uniqKey="Lin L" first="Low Yen" last="Lin">Low Yen Lin</name><affiliation><nlm:aff id="aff54"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yuqing, Li" sort="Yuqing, Li" uniqKey="Yuqing L" first="Li" last="Yuqing">Li Yuqing</name><affiliation><nlm:aff id="aff54"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Humphreys, Keith" sort="Humphreys, Keith" uniqKey="Humphreys K" first="Keith" last="Humphreys">Keith Humphreys</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="aff55"><addr-line>Institute for Cancer Studies, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Balasubramanian, Sabapathy P" sort="Balasubramanian, Sabapathy P" uniqKey="Balasubramanian S" first="Sabapathy P." last="Balasubramanian">Sabapathy P. Balasubramanian</name><affiliation><nlm:aff id="aff56"><addr-line>Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cross, Simon S" sort="Cross, Simon S" uniqKey="Cross S" first="Simon S." last="Cross">Simon S. Cross</name><affiliation><nlm:aff id="aff57"><addr-line>Academic Unit of Pathology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reed, Malcolm W R" sort="Reed, Malcolm W R" uniqKey="Reed M" first="Malcolm W. R." last="Reed">Malcolm W. R. Reed</name><affiliation><nlm:aff id="aff56"><addr-line>Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Blows, Fiona" sort="Blows, Fiona" uniqKey="Blows F" first="Fiona" last="Blows">Fiona Blows</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Driver, Kristy" sort="Driver, Kristy" uniqKey="Driver K" first="Kristy" last="Driver">Kristy Driver</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dunning, Alison" sort="Dunning, Alison" uniqKey="Dunning A" first="Alison" last="Dunning">Alison Dunning</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tyrer, Jonathan" sort="Tyrer, Jonathan" uniqKey="Tyrer J" first="Jonathan" last="Tyrer">Jonathan Tyrer</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ponder, Bruce A J" sort="Ponder, Bruce A J" uniqKey="Ponder B" first="Bruce A. J." last="Ponder">Bruce A. J. Ponder</name><affiliation><nlm:aff id="aff58"><addr-line>Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sangrajrang, Suleeporn" sort="Sangrajrang, Suleeporn" uniqKey="Sangrajrang S" first="Suleeporn" last="Sangrajrang">Suleeporn Sangrajrang</name><affiliation><nlm:aff id="aff59"><addr-line>Molecular Epidemiology Unit, National Cancer Institute, Ratchathewi, Bangkok, Thailand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brennan, Paul" sort="Brennan, Paul" uniqKey="Brennan P" first="Paul" last="Brennan">Paul Brennan</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mckay, James" sort="Mckay, James" uniqKey="Mckay J" first="James" last="Mckay">James Mckay</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Odefrey, Fabrice" sort="Odefrey, Fabrice" uniqKey="Odefrey F" first="Fabrice" last="Odefrey">Fabrice Odefrey</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gabrieau, Valerie" sort="Gabrieau, Valerie" uniqKey="Gabrieau V" first="Valerie" last="Gabrieau">Valerie Gabrieau</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sigurdson, Alice" sort="Sigurdson, Alice" uniqKey="Sigurdson A" first="Alice" last="Sigurdson">Alice Sigurdson</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Doody, Michele" sort="Doody, Michele" uniqKey="Doody M" first="Michele" last="Doody">Michele Doody</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Struewing, Jeffrey P" sort="Struewing, Jeffrey P" uniqKey="Struewing J" first="Jeffrey P." last="Struewing">Jeffrey P. Struewing</name><affiliation><nlm:aff id="aff61"><addr-line>Office of Population Genomics, National Human Genome Research Institute, Bethesda, Maryland, United Stated of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Alexander, Bruce" sort="Alexander, Bruce" uniqKey="Alexander B" first="Bruce" last="Alexander">Bruce Alexander</name><affiliation><nlm:aff id="aff62"><addr-line>Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></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="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul D" sort="Pharoah, Paul D" uniqKey="Pharoah P" first="Paul D." last="Pharoah">Paul D. Pharoah</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18437204</idno><idno type="pmc">2291027</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291027</idno><idno type="RBID">PMC:2291027</idno><idno type="doi">10.1371/journal.pgen.1000054</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">002870</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002870</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics</title><author><name sortKey="Garcia Closas, Montserrat" sort="Garcia Closas, Montserrat" uniqKey="Garcia Closas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></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="aff3"><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pooley, Karen" sort="Pooley, Karen" uniqKey="Pooley K" first="Karen" last="Pooley">Karen Pooley</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Morrison, Jonathan" sort="Morrison, Jonathan" uniqKey="Morrison J" first="Jonathan" last="Morrison">Jonathan Morrison</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Richesson, Douglas A" sort="Richesson, Douglas A" uniqKey="Richesson D" first="Douglas A." last="Richesson">Douglas A. Richesson</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Clinical Biochemistry, Herlev and Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>Department of Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G." last="Nordestgaard">B Rge G. Nordestgaard</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Clinical Biochemistry, Herlev and Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Axelsson, Christen K" sort="Axelsson, Christen K" uniqKey="Axelsson C" first="Christen K." last="Axelsson">Christen K. Axelsson</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Arias, Jose I" sort="Arias, Jose I" uniqKey="Arias J" first="Jose I." last="Arias">Jose I. Arias</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff9"><addr-line>Monte Naranco Hospital, Oviedo, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ribas, Gloria" sort="Ribas, Gloria" uniqKey="Ribas G" first="Gloria" last="Ribas">Gloria Ribas</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gonzalez Neira, Anna" sort="Gonzalez Neira, Anna" uniqKey="Gonzalez Neira A" first="Anna" last="González-Neira">Anna González-Neira</name><affiliation><nlm:aff id="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></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="aff8"><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zamora, Pilar" sort="Zamora, Pilar" uniqKey="Zamora P" first="Pilar" last="Zamora">Pilar Zamora</name><affiliation><nlm:aff id="aff10"><addr-line>La Paz Hospital, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="aff11"><addr-line>Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Justenhoven, Christina" sort="Justenhoven, Christina" uniqKey="Justenhoven C" first="Christina" last="Justenhoven">Christina Justenhoven</name><affiliation><nlm:aff id="aff11"><addr-line>Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany</addr-line></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="aff12"><addr-line>Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ko, Yon Dschun" sort="Ko, Yon Dschun" uniqKey="Ko Y" first="Yon-Dschun" last="Ko">Yon-Dschun Ko</name><affiliation><nlm:aff id="aff13"><addr-line>Evangelische Kliniken Bonn gGmhH Johanniter Krankenhaus, Bonn, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bruening, Thomas" sort="Bruening, Thomas" uniqKey="Bruening T" first="Thomas" last="Bruening">Thomas Bruening</name><affiliation><nlm:aff id="aff14"><addr-line>Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin, Ruhr University Bochum, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haas, Susanne" sort="Haas, Susanne" uniqKey="Haas S" first="Susanne" last="Haas">Susanne Haas</name><affiliation><nlm:aff id="aff15"><addr-line>Institute für Pathology, University Bonn, Bonn, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dork, Thilo" sort="Dork, Thilo" uniqKey="Dork T" first="Thilo" last="Dörk">Thilo Dörk</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schurmann, Peter" sort="Schurmann, Peter" uniqKey="Schurmann P" first="Peter" last="Schürmann">Peter Schürmann</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hillemanns, Peter" sort="Hillemanns, Peter" uniqKey="Hillemanns P" first="Peter" last="Hillemanns">Peter Hillemanns</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bogdanova, Natalia" sort="Bogdanova, Natalia" uniqKey="Bogdanova N" first="Natalia" last="Bogdanova">Natalia Bogdanova</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bremer, Michael" sort="Bremer, Michael" uniqKey="Bremer M" first="Michael" last="Bremer">Michael Bremer</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Karstens, Johann Hinrich" sort="Karstens, Johann Hinrich" uniqKey="Karstens J" first="Johann Hinrich" last="Karstens">Johann Hinrich Karstens</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fagerholm, Rainer" sort="Fagerholm, Rainer" uniqKey="Fagerholm R" first="Rainer" last="Fagerholm">Rainer Fagerholm</name><affiliation><nlm:aff id="aff3"><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aaltonen, Kirsimari" sort="Aaltonen, Kirsimari" uniqKey="Aaltonen K" first="Kirsimari" last="Aaltonen">Kirsimari Aaltonen</name><affiliation><nlm:aff id="aff3"><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><addr-line>Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></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="aff19"><addr-line>Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Von Smitten, Karl" sort="Von Smitten, Karl" uniqKey="Von Smitten K" first="Karl" last="Von Smitten">Karl Von Smitten</name><affiliation><nlm:aff id="aff20"><addr-line>Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Blomqvist, Carl" sort="Blomqvist, Carl" uniqKey="Blomqvist C" first="Carl" last="Blomqvist">Carl Blomqvist</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="aff21"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><addr-line>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uusitupa, Matti" sort="Uusitupa, Matti" uniqKey="Uusitupa M" first="Matti" last="Uusitupa">Matti Uusitupa</name><affiliation><nlm:aff id="aff23"><addr-line>Department of Public Health and Clinical Nutrition, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eskelinen, Matti" sort="Eskelinen, Matti" uniqKey="Eskelinen M" first="Matti" last="Eskelinen">Matti Eskelinen</name><affiliation><nlm:aff id="aff24"><addr-line>Department of Surgery, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tengstrom, Maria" sort="Tengstrom, Maria" uniqKey="Tengstrom M" first="Maria" last="Tengström">Maria Tengström</name><affiliation><nlm:aff id="aff25"><addr-line>Department of Oncology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><addr-line>Department of Oncology, Vaasa Central Hospital, Vaasa, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kosma, Veli Matti" sort="Kosma, Veli Matti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><nlm:aff id="aff21"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><addr-line>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kataja, Vesa" sort="Kataja, Vesa" uniqKey="Kataja V" first="Vesa" last="Kataja">Vesa Kataja</name><affiliation><nlm:aff id="aff25"><addr-line>Department of Oncology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><addr-line>Department of Oncology, Vaasa Central Hospital, Vaasa, Finland</addr-line></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="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></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="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beesley, Jonathan" sort="Beesley, Jonathan" uniqKey="Beesley J" first="Jonathan" last="Beesley">Jonathan Beesley</name><affiliation><nlm:aff id="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chen, Xiaoqing" sort="Chen, Xiaoqing" uniqKey="Chen X" first="Xiaoqing" last="Chen">Xiaoqing Chen</name><affiliation><nlm:aff id="aff27"><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Devilee, Peter" sort="Devilee, Peter" uniqKey="Devilee P" first="Peter" last="Devilee">Peter Devilee</name><affiliation><nlm:aff id="aff29"><addr-line>Departments of Human Genetics and Pathology, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Asperen, Christi J" sort="Van Asperen, Christi J" uniqKey="Van Asperen C" first="Christi J." last="Van Asperen">Christi J. Van Asperen</name><affiliation><nlm:aff id="aff30"><addr-line>Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jacobi, Catharina E" sort="Jacobi, Catharina E" uniqKey="Jacobi C" first="Catharina E." last="Jacobi">Catharina E. Jacobi</name><affiliation><nlm:aff id="aff31"><addr-line>Department of Medical Decision Making, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tollenaar, Rob A E M" sort="Tollenaar, Rob A E M" uniqKey="Tollenaar R" first="Rob A. E. M." last="Tollenaar">Rob A. E. M. Tollenaar</name><affiliation><nlm:aff id="aff32"><addr-line>Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huijts, Petra E A" sort="Huijts, Petra E A" uniqKey="Huijts P" first="Petra E. A." last="Huijts">Petra E. A. Huijts</name><affiliation><nlm:aff id="aff33"><addr-line>Department of Medical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Klijn, Jan G M" sort="Klijn, Jan G M" uniqKey="Klijn J" first="Jan G. M." last="Klijn">Jan G. M. Klijn</name><affiliation><nlm:aff id="aff33"><addr-line>Department of Medical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="aff34"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kropp, Silke" sort="Kropp, Silke" uniqKey="Kropp S" first="Silke" last="Kropp">Silke Kropp</name><affiliation><nlm:aff id="aff34"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Slanger, Tracy" sort="Slanger, Tracy" uniqKey="Slanger T" first="Tracy" last="Slanger">Tracy Slanger</name><affiliation><nlm:aff id="aff34"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flesch Janys, Dieter" sort="Flesch Janys, Dieter" uniqKey="Flesch Janys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="aff35"><addr-line>Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mutschelknauss, Elke" sort="Mutschelknauss, Elke" uniqKey="Mutschelknauss E" first="Elke" last="Mutschelknauss">Elke Mutschelknauss</name><affiliation><nlm:aff id="aff35"><addr-line>Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Salazar, Ramona" sort="Salazar, Ramona" uniqKey="Salazar R" first="Ramona" last="Salazar">Ramona Salazar</name><affiliation><nlm:aff id="aff36"><addr-line>Bioglobe GmbH, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang Gohrke, Shan" sort="Wang Gohrke, Shan" uniqKey="Wang Gohrke S" first="Shan" last="Wang-Gohrke">Shan Wang-Gohrke</name><affiliation><nlm:aff id="aff37"><addr-line>Molecular Biology Laboratory, Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus" sort="Couch, Fergus" uniqKey="Couch F" first="Fergus" last="Couch">Fergus Couch</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Goode, Ellen L" sort="Goode, Ellen L" uniqKey="Goode E" first="Ellen L." last="Goode">Ellen L. Goode</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E." last="Olson">Janet E. Olson</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vachon, Celine" sort="Vachon, Celine" uniqKey="Vachon C" first="Celine" last="Vachon">Celine Vachon</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fredericksen, Zachary S" sort="Fredericksen, Zachary S" uniqKey="Fredericksen Z" first="Zachary S." last="Fredericksen">Zachary S. Fredericksen</name><affiliation><nlm:aff id="aff38"><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff39"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><affiliation><nlm:aff id="aff39"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name><affiliation><nlm:aff id="aff39"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></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="aff40"><addr-line>Centre for MEGA Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="English, Dallas R" sort="English, Dallas R" uniqKey="English D" first="Dallas R." last="English">Dallas R. English</name><affiliation><nlm:aff id="aff40"><addr-line>Centre for MEGA Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></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="aff41"><addr-line>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Henderson, Brian E" sort="Henderson, Brian E" uniqKey="Henderson B" first="Brian E." last="Henderson">Brian E. Henderson</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kolonel, Laurence N" sort="Kolonel, Laurence N" uniqKey="Kolonel L" first="Laurence N." last="Kolonel">Laurence N. Kolonel</name><affiliation><nlm:aff id="aff43"><addr-line>Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Le Marchand, Loic" sort="Le Marchand, Loic" uniqKey="Le Marchand L" first="Loic" last="Le Marchand">Loic Le Marchand</name><affiliation><nlm:aff id="aff43"><addr-line>Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stram, Daniel O" sort="Stram, Daniel O" uniqKey="Stram D" first="Daniel O." last="Stram">Daniel O. Stram</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hunter, David J" sort="Hunter, David J" uniqKey="Hunter D" first="David J." last="Hunter">David J. Hunter</name><affiliation><nlm:aff id="aff45"><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hankinson, Susan E" sort="Hankinson, Susan E" uniqKey="Hankinson S" first="Susan E." last="Hankinson">Susan E. Hankinson</name><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, David G" sort="Cox, David G" uniqKey="Cox D" first="David G." last="Cox">David G. Cox</name><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff47"><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tamimi, Rulla" sort="Tamimi, Rulla" uniqKey="Tamimi R" first="Rulla" last="Tamimi">Rulla Tamimi</name><affiliation><nlm:aff id="aff46"><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kraft, Peter" sort="Kraft, Peter" uniqKey="Kraft P" first="Peter" last="Kraft">Peter Kraft</name><affiliation><nlm:aff id="aff47"><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sherman, Mark E" sort="Sherman, Mark E" uniqKey="Sherman M" first="Mark E." last="Sherman">Mark E. Sherman</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="aff48"><addr-line>Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lissowska, Jolanta" sort="Lissowska, Jolanta" uniqKey="Lissowska J" first="Jolanta" last="Lissowska">Jolanta Lissowska</name><affiliation><nlm:aff id="aff49"><addr-line>Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brinton, Louise A" sort="Brinton, Louise A" uniqKey="Brinton L" first="Louise A." last="Brinton">Louise A. Brinton</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peplonska, Beata" sort="Peplonska, Beata" uniqKey="Peplonska B" first="Beata" last="Peplonska">Beata Peplonska</name><affiliation><nlm:aff id="aff50"><addr-line>Nofer Institute of Occupational Medicine, Lodz, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Klijn, Jan G M" sort="Klijn, Jan G M" uniqKey="Klijn J" first="Jan G. M." last="Klijn">Jan G. M. Klijn</name><affiliation><nlm:aff id="aff51"><addr-line>Daniel den Hoed Cancer Center, Erasmus Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hooning, Maartje J" sort="Hooning, Maartje J" uniqKey="Hooning M" first="Maartje J." last="Hooning">Maartje J. Hooning</name><affiliation><nlm:aff id="aff51"><addr-line>Daniel den Hoed Cancer Center, Erasmus Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meijers Heijboer, Han" sort="Meijers Heijboer, Han" uniqKey="Meijers Heijboer H" first="Han" last="Meijers-Heijboer">Han Meijers-Heijboer</name><affiliation><nlm:aff id="aff52"><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Collee, J Margriet" sort="Collee, J Margriet" uniqKey="Collee J" first="J. Margriet" last="Collee">J. Margriet Collee</name><affiliation><nlm:aff id="aff52"><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Den Ouweland, Ans" sort="Van Den Ouweland, Ans" uniqKey="Van Den Ouweland A" first="Ans" last="Van Den Ouweland">Ans Van Den Ouweland</name><affiliation><nlm:aff id="aff52"><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="Andre G." last="Uitterlinden">Andre G. Uitterlinden</name><affiliation><nlm:aff id="aff53"><addr-line>Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name><affiliation><nlm:aff id="aff54"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lin, Low Yen" sort="Lin, Low Yen" uniqKey="Lin L" first="Low Yen" last="Lin">Low Yen Lin</name><affiliation><nlm:aff id="aff54"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yuqing, Li" sort="Yuqing, Li" uniqKey="Yuqing L" first="Li" last="Yuqing">Li Yuqing</name><affiliation><nlm:aff id="aff54"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Humphreys, Keith" sort="Humphreys, Keith" uniqKey="Humphreys K" first="Keith" last="Humphreys">Keith Humphreys</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="aff55"><addr-line>Institute for Cancer Studies, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Balasubramanian, Sabapathy P" sort="Balasubramanian, Sabapathy P" uniqKey="Balasubramanian S" first="Sabapathy P." last="Balasubramanian">Sabapathy P. Balasubramanian</name><affiliation><nlm:aff id="aff56"><addr-line>Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cross, Simon S" sort="Cross, Simon S" uniqKey="Cross S" first="Simon S." last="Cross">Simon S. Cross</name><affiliation><nlm:aff id="aff57"><addr-line>Academic Unit of Pathology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reed, Malcolm W R" sort="Reed, Malcolm W R" uniqKey="Reed M" first="Malcolm W. R." last="Reed">Malcolm W. R. Reed</name><affiliation><nlm:aff id="aff56"><addr-line>Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Blows, Fiona" sort="Blows, Fiona" uniqKey="Blows F" first="Fiona" last="Blows">Fiona Blows</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Driver, Kristy" sort="Driver, Kristy" uniqKey="Driver K" first="Kristy" last="Driver">Kristy Driver</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dunning, Alison" sort="Dunning, Alison" uniqKey="Dunning A" first="Alison" last="Dunning">Alison Dunning</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tyrer, Jonathan" sort="Tyrer, Jonathan" uniqKey="Tyrer J" first="Jonathan" last="Tyrer">Jonathan Tyrer</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ponder, Bruce A J" sort="Ponder, Bruce A J" uniqKey="Ponder B" first="Bruce A. J." last="Ponder">Bruce A. J. Ponder</name><affiliation><nlm:aff id="aff58"><addr-line>Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sangrajrang, Suleeporn" sort="Sangrajrang, Suleeporn" uniqKey="Sangrajrang S" first="Suleeporn" last="Sangrajrang">Suleeporn Sangrajrang</name><affiliation><nlm:aff id="aff59"><addr-line>Molecular Epidemiology Unit, National Cancer Institute, Ratchathewi, Bangkok, Thailand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brennan, Paul" sort="Brennan, Paul" uniqKey="Brennan P" first="Paul" last="Brennan">Paul Brennan</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mckay, James" sort="Mckay, James" uniqKey="Mckay J" first="James" last="Mckay">James Mckay</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Odefrey, Fabrice" sort="Odefrey, Fabrice" uniqKey="Odefrey F" first="Fabrice" last="Odefrey">Fabrice Odefrey</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gabrieau, Valerie" sort="Gabrieau, Valerie" uniqKey="Gabrieau V" first="Valerie" last="Gabrieau">Valerie Gabrieau</name><affiliation><nlm:aff id="aff60"><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sigurdson, Alice" sort="Sigurdson, Alice" uniqKey="Sigurdson A" first="Alice" last="Sigurdson">Alice Sigurdson</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Doody, Michele" sort="Doody, Michele" uniqKey="Doody M" first="Michele" last="Doody">Michele Doody</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Struewing, Jeffrey P" sort="Struewing, Jeffrey P" uniqKey="Struewing J" first="Jeffrey P." last="Struewing">Jeffrey P. Struewing</name><affiliation><nlm:aff id="aff61"><addr-line>Office of Population Genomics, National Human Genome Research Institute, Bethesda, Maryland, United Stated of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Alexander, Bruce" sort="Alexander, Bruce" uniqKey="Alexander B" first="Bruce" last="Alexander">Bruce Alexander</name><affiliation><nlm:aff id="aff62"><addr-line>Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></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="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul D" sort="Pharoah, Paul D" uniqKey="Pharoah P" first="Paul D." last="Pharoah">Paul D. Pharoah</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Genetics</title><idno type="ISSN">1553-7390</idno><idno type="eISSN">1553-7404</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (<italic>FGFR2</italic>), trinucleotide repeat containing 9 (<italic>TNRC9</italic>), mitogen-activated protein kinase 3 K1 (<italic>MAP3K1</italic>), 8q24, and lymphocyte-specific protein 1 (<italic>LSP1</italic>)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in <italic>FGFR2</italic> was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10<sup>−13</sup>). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10<sup>−5</sup>, 10<sup>−8</sup>, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10<sup>−4</sup>, respectively). The differences in the associations between SNPs in <italic>FGFR2</italic> and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in <italic>TNRC9</italic> (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Anderson, Wf" uniqKey="Anderson W">WF Anderson</name></author><author><name sortKey="Jatoi, I" uniqKey="Jatoi I">I Jatoi</name></author><author><name sortKey="Devesa, Ss" uniqKey="Devesa S">SS Devesa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ma, H" uniqKey="Ma H">H Ma</name></author><author><name sortKey="Bernstein, L" uniqKey="Bernstein L">L Bernstein</name></author><author><name sortKey="Pike, Mc" uniqKey="Pike M">MC Pike</name></author><author><name sortKey="Ursin, G" uniqKey="Ursin G">G Ursin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reeves, Gk" uniqKey="Reeves G">GK Reeves</name></author><author><name sortKey="Beral, V" uniqKey="Beral V">V 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosgen</journal-id><journal-title-group><journal-title>PLoS Genetics</journal-title></journal-title-group><issn pub-type="ppub">1553-7390</issn><issn pub-type="epub">1553-7404</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18437204</article-id><article-id pub-id-type="pmc">2291027</article-id><article-id pub-id-type="publisher-id">07-PLGE-RA-0661R5</article-id><article-id pub-id-type="doi">10.1371/journal.pgen.1000054</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Genetics and Genomics/Genetics of Disease</subject><subject>Oncology/Breast Cancer</subject></subj-group></article-categories><title-group><article-title>Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics</article-title><alt-title alt-title-type="running-head">Breast Cancer Susceptibility and Pathology</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Garcia-Closas</surname><given-names>Montserrat</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Per</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nevanlinna</surname><given-names>Heli</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pooley</surname><given-names>Karen</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Morrison</surname><given-names>Jonathan</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Richesson</surname><given-names>Douglas A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bojesen</surname><given-names>Stig E.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nordestgaard</surname><given-names>Børge G.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Axelsson</surname><given-names>Christen K.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Arias</surname><given-names>Jose I.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Milne</surname><given-names>Roger L.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ribas</surname><given-names>Gloria</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>González-Neira</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Benítez</surname><given-names>Javier</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zamora</surname><given-names>Pilar</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brauch</surname><given-names>Hiltrud</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Justenhoven</surname><given-names>Christina</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hamann</surname><given-names>Ute</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ko</surname><given-names>Yon-Dschun</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bruening</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haas</surname><given-names>Susanne</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dörk</surname><given-names>Thilo</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schürmann</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hillemanns</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bogdanova</surname><given-names>Natalia</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bremer</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Karstens</surname><given-names>Johann Hinrich</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fagerholm</surname><given-names>Rainer</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Aaltonen</surname><given-names>Kirsimari</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Aittomäki</surname><given-names>Kristiina</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>von Smitten</surname><given-names>Karl</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Blomqvist</surname><given-names>Carl</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mannermaa</surname><given-names>Arto</given-names></name><xref ref-type="aff" rid="aff21"><sup>21</sup></xref><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Uusitupa</surname><given-names>Matti</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eskelinen</surname><given-names>Matti</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tengström</surname><given-names>Maria</given-names></name><xref ref-type="aff" rid="aff25"><sup>25</sup></xref><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kosma</surname><given-names>Veli-Matti</given-names></name><xref ref-type="aff" rid="aff21"><sup>21</sup></xref><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kataja</surname><given-names>Vesa</given-names></name><xref ref-type="aff" rid="aff25"><sup>25</sup></xref><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chenevix-Trench</surname><given-names>Georgia</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Spurdle</surname><given-names>Amanda B.</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beesley</surname><given-names>Jonathan</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Xiaoqing</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Australian Ovarian Cancer Management Group</surname><given-names></given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref><xref ref-type="aff" rid="aff28"><sup>28</sup></xref></contrib><contrib contrib-type="author"><name><surname>The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer</surname><given-names></given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref></contrib><contrib contrib-type="author"><name><surname>Devilee</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff29"><sup>29</sup></xref></contrib><contrib contrib-type="author"><name><surname>van Asperen</surname><given-names>Christi J.</given-names></name><xref ref-type="aff" rid="aff30"><sup>30</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jacobi</surname><given-names>Catharina E.</given-names></name><xref ref-type="aff" rid="aff31"><sup>31</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tollenaar</surname><given-names>Rob A. E. M.</given-names></name><xref ref-type="aff" rid="aff32"><sup>32</sup></xref></contrib><contrib contrib-type="author"><name><surname>Huijts</surname><given-names>Petra E.A.</given-names></name><xref ref-type="aff" rid="aff33"><sup>33</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klijn</surname><given-names>Jan G. M.</given-names></name><xref ref-type="aff" rid="aff33"><sup>33</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chang-Claude</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="aff34"><sup>34</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kropp</surname><given-names>Silke</given-names></name><xref ref-type="aff" rid="aff34"><sup>34</sup></xref></contrib><contrib contrib-type="author"><name><surname>Slanger</surname><given-names>Tracy</given-names></name><xref ref-type="aff" rid="aff34"><sup>34</sup></xref></contrib><contrib contrib-type="author"><name><surname>Flesch-Janys</surname><given-names>Dieter</given-names></name><xref ref-type="aff" rid="aff35"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mutschelknauss</surname><given-names>Elke</given-names></name><xref ref-type="aff" rid="aff35"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Salazar</surname><given-names>Ramona</given-names></name><xref ref-type="aff" rid="aff36"><sup>36</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang-Gohrke</surname><given-names>Shan</given-names></name><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>Couch</surname><given-names>Fergus</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Goode</surname><given-names>Ellen L.</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Olson</surname><given-names>Janet E.</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vachon</surname><given-names>Celine</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fredericksen</surname><given-names>Zachary S.</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Graham G.</given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Baglietto</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Severi</surname><given-names>Gianluca</given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>John L.</given-names></name><xref ref-type="aff" rid="aff40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>English</surname><given-names>Dallas R.</given-names></name><xref ref-type="aff" rid="aff40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>Melissa C.</given-names></name><xref ref-type="aff" rid="aff41"><sup>41</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haiman</surname><given-names>Christopher A.</given-names></name><xref ref-type="aff" rid="aff42"><sup>42</sup></xref></contrib><contrib contrib-type="author"><name><surname>Henderson</surname><given-names>Brian E.</given-names></name><xref ref-type="aff" rid="aff42"><sup>42</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kolonel</surname><given-names>Laurence N.</given-names></name><xref ref-type="aff" rid="aff43"><sup>43</sup></xref></contrib><contrib contrib-type="author"><name><surname>Le Marchand</surname><given-names>Loic</given-names></name><xref ref-type="aff" rid="aff43"><sup>43</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stram</surname><given-names>Daniel O.</given-names></name><xref ref-type="aff" rid="aff44"><sup>44</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hunter</surname><given-names>David J.</given-names></name><xref ref-type="aff" rid="aff45"><sup>45</sup></xref><xref ref-type="aff" rid="aff46"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hankinson</surname><given-names>Susan E.</given-names></name><xref ref-type="aff" rid="aff46"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cox</surname><given-names>David G.</given-names></name><xref ref-type="aff" rid="aff46"><sup>46</sup></xref><xref ref-type="aff" rid="aff47"><sup>47</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tamimi</surname><given-names>Rulla</given-names></name><xref ref-type="aff" rid="aff46"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kraft</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff47"><sup>47</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sherman</surname><given-names>Mark E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chanock</surname><given-names>Stephen J.</given-names></name><xref ref-type="aff" rid="aff48"><sup>48</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lissowska</surname><given-names>Jolanta</given-names></name><xref ref-type="aff" rid="aff49"><sup>49</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brinton</surname><given-names>Louise A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peplonska</surname><given-names>Beata</given-names></name><xref ref-type="aff" rid="aff50"><sup>50</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klijn</surname><given-names>Jan G. M.</given-names></name><xref ref-type="aff" rid="aff51"><sup>51</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hooning</surname><given-names>Maartje J.</given-names></name><xref ref-type="aff" rid="aff51"><sup>51</sup></xref></contrib><contrib contrib-type="author"><name><surname>Meijers-Heijboer</surname><given-names>Han</given-names></name><xref ref-type="aff" rid="aff52"><sup>52</sup></xref></contrib><contrib contrib-type="author"><name><surname>Collee</surname><given-names>J. Margriet</given-names></name><xref ref-type="aff" rid="aff52"><sup>52</sup></xref></contrib><contrib contrib-type="author"><name><surname>van den Ouweland</surname><given-names>Ans</given-names></name><xref ref-type="aff" rid="aff52"><sup>52</sup></xref></contrib><contrib contrib-type="author"><name><surname>Uitterlinden</surname><given-names>Andre G.</given-names></name><xref ref-type="aff" rid="aff53"><sup>53</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jianjun</given-names></name><xref ref-type="aff" rid="aff54"><sup>54</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Low Yen</given-names></name><xref ref-type="aff" rid="aff54"><sup>54</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yuqing</surname><given-names>Li</given-names></name><xref ref-type="aff" rid="aff54"><sup>54</sup></xref></contrib><contrib contrib-type="author"><name><surname>Humphreys</surname><given-names>Keith</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Czene</surname><given-names>Kamila</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cox</surname><given-names>Angela</given-names></name><xref ref-type="aff" rid="aff55"><sup>55</sup></xref></contrib><contrib contrib-type="author"><name><surname>Balasubramanian</surname><given-names>Sabapathy P.</given-names></name><xref ref-type="aff" rid="aff56"><sup>56</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cross</surname><given-names>Simon S.</given-names></name><xref ref-type="aff" rid="aff57"><sup>57</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reed</surname><given-names>Malcolm W. R.</given-names></name><xref ref-type="aff" rid="aff56"><sup>56</sup></xref></contrib><contrib contrib-type="author"><name><surname>Blows</surname><given-names>Fiona</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Driver</surname><given-names>Kristy</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dunning</surname><given-names>Alison</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tyrer</surname><given-names>Jonathan</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ponder</surname><given-names>Bruce A. J.</given-names></name><xref ref-type="aff" rid="aff58"><sup>58</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sangrajrang</surname><given-names>Suleeporn</given-names></name><xref ref-type="aff" rid="aff59"><sup>59</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brennan</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="aff60"><sup>60</sup></xref></contrib><contrib contrib-type="author"><name><surname>McKay</surname><given-names>James</given-names></name><xref ref-type="aff" rid="aff60"><sup>60</sup></xref></contrib><contrib contrib-type="author"><name><surname>Odefrey</surname><given-names>Fabrice</given-names></name><xref ref-type="aff" rid="aff60"><sup>60</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gabrieau</surname><given-names>Valerie</given-names></name><xref ref-type="aff" rid="aff60"><sup>60</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sigurdson</surname><given-names>Alice</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Doody</surname><given-names>Michele</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Struewing</surname><given-names>Jeffrey P.</given-names></name><xref ref-type="aff" rid="aff61"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Alexander</surname><given-names>Bruce</given-names></name><xref ref-type="aff" rid="aff62"><sup>62</sup></xref></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Douglas F.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pharoah</surname><given-names>Paul D.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Marylan, United States of America</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Department of Clinical Biochemistry, Herlev and Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Department of Bispebjerg University Hospitals, University of Copenhagen, Denmark</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Denmark</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Spanish National Cancer Centre, Madrid, Spain</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Monte Naranco Hospital, Oviedo, Spain</addr-line></aff><aff id="aff10"><label>10</label><addr-line>La Paz Hospital, Madrid, Spain</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Evangelische Kliniken Bonn gGmhH Johanniter Krankenhaus, Bonn, Germany</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin, Ruhr University Bochum, Germany</addr-line></aff><aff id="aff15"><label>15</label><addr-line>Institute für Pathology, University Bonn, Bonn, Germany</addr-line></aff><aff id="aff16"><label>16</label><addr-line>Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany</addr-line></aff><aff id="aff17"><label>17</label><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></aff><aff id="aff18"><label>18</label><addr-line>Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland</addr-line></aff><aff id="aff19"><label>19</label><addr-line>Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland</addr-line></aff><aff id="aff20"><label>20</label><addr-line>Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland</addr-line></aff><aff id="aff21"><label>21</label><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></aff><aff id="aff22"><label>22</label><addr-line>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></aff><aff id="aff23"><label>23</label><addr-line>Department of Public Health and Clinical Nutrition, Biocenter Kuopio, University of Kuopio, Kuopio, Finland</addr-line></aff><aff id="aff24"><label>24</label><addr-line>Department of Surgery, Kuopio University Hospital, Kuopio, Finland</addr-line></aff><aff id="aff25"><label>25</label><addr-line>Department of Oncology, Kuopio University Hospital, Kuopio, Finland</addr-line></aff><aff id="aff26"><label>26</label><addr-line>Department of Oncology, Vaasa Central Hospital, Vaasa, Finland</addr-line></aff><aff id="aff27"><label>27</label><addr-line>The Queensland Institute of Medical Research Post Office, Royal Brisbane Hospital, Herston, Queensland, Australia</addr-line></aff><aff id="aff28"><label>28</label><addr-line>Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia</addr-line></aff><aff id="aff29"><label>29</label><addr-line>Departments of Human Genetics and Pathology, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff30"><label>30</label><addr-line>Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff31"><label>31</label><addr-line>Department of Medical Decision Making, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff32"><label>32</label><addr-line>Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff33"><label>33</label><addr-line>Department of Medical Oncology, Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff34"><label>34</label><addr-line>Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany</addr-line></aff><aff id="aff35"><label>35</label><addr-line>Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></aff><aff id="aff36"><label>36</label><addr-line>Bioglobe GmbH, Hamburg, Germany</addr-line></aff><aff id="aff37"><label>37</label><addr-line>Molecular Biology Laboratory, Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></aff><aff id="aff38"><label>38</label><addr-line>Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America</addr-line></aff><aff id="aff39"><label>39</label><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia</addr-line></aff><aff id="aff40"><label>40</label><addr-line>Centre for MEGA Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></aff><aff id="aff41"><label>41</label><addr-line>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia</addr-line></aff><aff id="aff42"><label>42</label><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></aff><aff id="aff43"><label>43</label><addr-line>Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, United States of America</addr-line></aff><aff id="aff44"><label>44</label><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></aff><aff id="aff45"><label>45</label><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff46"><label>46</label><addr-line>Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff47"><label>47</label><addr-line>Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff48"><label>48</label><addr-line>Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland, United States of America</addr-line></aff><aff id="aff49"><label>49</label><addr-line>Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland</addr-line></aff><aff id="aff50"><label>50</label><addr-line>Nofer Institute of Occupational Medicine, Lodz, Poland</addr-line></aff><aff id="aff51"><label>51</label><addr-line>Daniel den Hoed Cancer Center, Erasmus Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</addr-line></aff><aff id="aff52"><label>52</label><addr-line>Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff53"><label>53</label><addr-line>Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff54"><label>54</label><addr-line>Human Genetics, Genome Institute of Singapore, Singapore</addr-line></aff><aff id="aff55"><label>55</label><addr-line>Institute for Cancer Studies, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></aff><aff id="aff56"><label>56</label><addr-line>Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></aff><aff id="aff57"><label>57</label><addr-line>Academic Unit of Pathology, Sheffield University Medical School, Sheffield, United Kingdom</addr-line></aff><aff id="aff58"><label>58</label><addr-line>Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom</addr-line></aff><aff id="aff59"><label>59</label><addr-line>Molecular Epidemiology Unit, National Cancer Institute, Ratchathewi, Bangkok, Thailand</addr-line></aff><aff id="aff60"><label>60</label><addr-line>International Agency for Research on Cancer, Lyon, France</addr-line></aff><aff id="aff61"><label>61</label><addr-line>Office of Population Genomics, National Human Genome Research Institute, Bethesda, Maryland, United Stated of America</addr-line></aff><aff id="aff62"><label>62</label><addr-line>Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Leal</surname><given-names>Suzanne M.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">Baylor College of Medicine, United States of America</aff><author-notes><corresp id="cor1">* E-mail: <email>montse@nih.gov</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: M. Garcia-Closas, P. Hall, S. Bojesen, B. Nordestgaard, C. Axelsson, T. Dörk, J. Chang-Claude, D. Flesch-Janys, D. Hunter, S. Hankinson, D. Cox, R. Tamimi, P. Kraft, P. Brennan, J. McKay, D. Easton, P. Pharoah. Performed the experiments: K. Pooley, R. Milne, G. Ribas, A. González-Neira, J. Benítez, H. Brauch, C. Justenhoven, T. Dörk, P. Schürmann, N. Bogdanova, A. Mannermaa, J. Beesley, X. Chen, J. Chang-Claude, R. Salazar, S. Wang-Gohrke, F. Couch, M. Southey, D. Hunter, D. Cox, S. Chanock, J. Liu, A. Dunning, F. Odefrey, J. Struewing. Analyzed the data: M. Garcia-Closas, D. Richesson, T. Dörk, M. Tengström, V. Kataja, P. Huijts, S. Kropp, D. Flesch-Janys, P. Kraft, J. Tyrer, V. Gabrieau. Contributed reagents/materials/analysis tools: M. Garcia-Closas, P. Hall, H. Nevanlinna, K. Pooley, J. Morrison, S. Bojesen, B. Nordestgaard, C. Axelsson, H. Brauch, P. Hillemanns, M. Bremer, J. Karstens, R. Fagerholm, K. Aaltonen, K. Aittomäki, K. von Smitten, C. Blomqvist, M. Uusitupa, M. Eskelinen, V. Kosma, G. Chenevix-Trench, A. Spurdle, Australian Ovarian Cancer Management Group, The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, P. Devilee, C. van Asperen, R. Tollenaar, J. Chang-Claude, D. Flesch-Janys, F. Couch, J. Olson, G. Giles, C. Haiman, B. Henderson, L. Kolonel, L. Le Marchand, D. Stram, A. Uitterlinden, J. Liu, K. Humphreys, K. Czene, J. Struewing. Wrote the paper: M. Garcia-Closas, P. Hall, H. Nevanlinna, P. Pharoah. Study design/data collection: M. Garcia-Closas, P. Hall, H. Nevanlinna, J. Morrison, J. Arias, P. Zamora, H. Brauch, C. Justenhoven, U. Hamann, Y. Ko, T. Bruening, S. Haas, R. Fagerholm, K. Aaltonen, A. Mannermaa, M. Uusitupa, M. Eskelinen, M. Tengström, V. Kosma, V. Kataja, G. Chenevix-Trench, A. Spurdle, C. van Asperen, C. Jacobi, R. Tollenaar, J. Klijn, T. Slanger, E. Mutschelknauss, F. Couch, E. Goode, J. Olson, C. Vachon, Z. Fredericksen, G. Giles, L. Baglietto, G. Severi, J. Hopper, D. English, M. Southey, C. Haiman, B. Henderson, L. Kolonel, L. Le Marchand, D. Stram, D. Hunter, S. Hankinson, R. Tamimi, M. Sherman, J. Lissowska, L. Brinton, B. Peplonska, J. Klijn, M. Hooning, H. Meijers-Heijboer, J. Collee, A. Ouweland, J. Liu, L. Lin, L. Yuqing, A. Cox, S. Balasubramanian, M. Reed, F. Blows, K. Driver, A. Dunning, B. Ponder, S. Sangrajrang, A. Sigurdson, M. Doody, B. Alexander, D. Easton, P. Pharoah. Pathology review: J. Arias, P. Zamora, S. Haas, M. Bremer, V. Kosma, M. Sherman, S. Cross, F. Blows, K. Driver.</p></fn></author-notes><pub-date pub-type="collection"><month>4</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>25</day><month>4</month><year>2008</year></pub-date><volume>4</volume><issue>4</issue><elocation-id>e1000054</elocation-id><history><date date-type="received"><day>16</day><month>8</month><year>2007</year></date><date date-type="accepted"><day>18</day><month>3</month><year>2008</year></date></history><permissions><copyright-statement>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</copyright-statement><copyright-year>2008</copyright-year><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p></license></permissions><abstract><p>A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (<italic>FGFR2</italic>), trinucleotide repeat containing 9 (<italic>TNRC9</italic>), mitogen-activated protein kinase 3 K1 (<italic>MAP3K1</italic>), 8q24, and lymphocyte-specific protein 1 (<italic>LSP1</italic>)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in <italic>FGFR2</italic> was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10<sup>−13</sup>). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10<sup>−5</sup>, 10<sup>−8</sup>, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10<sup>−4</sup>, respectively). The differences in the associations between SNPs in <italic>FGFR2</italic> and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in <italic>TNRC9</italic> (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>This report from the Breast Cancer Association Consortium evaluates whether common variants in five recently identified breast cancer susceptibility loci (<italic>FGFR2</italic>, <italic>TNRC9</italic>, <italic>MAP3K1</italic>, 8q24, and <italic>LSP1</italic>) influence the clinical presentation of breast cancer and survival after diagnosis. We studied these susceptibility loci in relation to clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls of European or Asian origin from 20 studies. The association, with overall survival, was evaluated in 13,527 cases from 13 studies. The most notable findings were that the genetic variants in the fibroblast growth factor receptor 2 (<italic>FGFR2</italic>) gene and the 8q24 region were more strongly related to ER-positive than ER-negative disease, and to low rather than high grade tumors. The loci did not significantly influence survival after accounting for known prognostic factors. Analyses indicated that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative diseases are biologically distinct tumors. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.</p></abstract><counts><page-count count="10"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Breast cancers vary greatly in clinical behavior, morphological appearance, and molecular alterations. Accumulating epidemiologic data also suggest that different types of breast cancers have different risk factor profiles and thus might result from different etiologic pathways (which might be shared by different tumor types or be type specific). Notably, age-specific incidence rates <xref rid="pgen.1000054-Anderson1" ref-type="bibr">[1]</xref> and the strength of the associations with known risk factors for breast cancer <xref rid="pgen.1000054-Ma1" ref-type="bibr">[2]</xref>–<xref rid="pgen.1000054-Althuis1" ref-type="bibr">[4]</xref> differ by clinically important tumor characteristics. Evidence that genetic factors can also influence tumor type is provided by the fact that carriers of highly penetrant mutations in <italic>BRCA1</italic> are more likely to be diagnosed with basal breast tumors which are estrogen receptor (ER) negative, progesterone receptor (PR) negative and HER2 negative <xref rid="pgen.1000054-Sorlie1" ref-type="bibr">[5]</xref>. This raises the possibility that other susceptibility loci may also be associated with specific subtypes of breast cancer.</p><p>We recently performed a two-stage genome-wide association study (GWAS) in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in 21,860 cases and 22,578 controls from 22 studies, identifying single nucleotide polymorphisms (SNPs) in 5 loci associated with breast cancer risk <xref rid="pgen.1000054-Easton1" ref-type="bibr">[6]</xref>. Of the five loci identified, 4 were within genes or linkage disequilibrium (LD) blocks containing genes, including: 1) rs2981582 in the <italic>FGFR2</italic> gene coding for a receptor tyrosine kinase that plays an important role in mammary gland development <xref rid="pgen.1000054-Dillon1" ref-type="bibr">[7]</xref>, has been implicated in carcinogenesis <xref rid="pgen.1000054-Grose1" ref-type="bibr">[8]</xref>, and is amplified <xref rid="pgen.1000054-Heiskanen1" ref-type="bibr">[9]</xref>–<xref rid="pgen.1000054-Gudmundsson1" ref-type="bibr">[11]</xref> or over-expressed <xref rid="pgen.1000054-PenaultLlorca1" ref-type="bibr">[12]</xref> in up to 10% of breast tumors; 2) rs3803662 in a LD block containing <italic>TNRC9</italic> (also known <italic>TOX3</italic>) and the hypothetical gene <italic>LOC643714</italic>; 3) rs889312 in a LD block containing <italic>MAP3K1</italic> and two hypothetical genes (<italic>MGC33648</italic> and mesoderm induction early response 1, family member 3 (<italic>MIER3</italic>)); and 4) rs3817198 in the <italic>LSP1</italic> gene. The fifth SNP (rs13281615) lies on a region of 8q24 that does not contain known genes, but has multiple independent variants associated with prostate <xref rid="pgen.1000054-Yeager1" ref-type="bibr">[13]</xref>,<xref rid="pgen.1000054-Haiman1" ref-type="bibr">[14]</xref> and colorectal <xref rid="pgen.1000054-Zanke1" ref-type="bibr">[15]</xref>–<xref rid="pgen.1000054-Gruber1" ref-type="bibr">[18]</xref> cancer risk. Two additional genome wide association studies also recently identified SNPs in <italic>FGFR2</italic><xref rid="pgen.1000054-Hunter1" ref-type="bibr">[19]</xref> and <italic>TNRC9</italic><xref rid="pgen.1000054-Stacey1" ref-type="bibr">[20]</xref> as breast cancer susceptibility loci.</p><p>We used the large data resource provided by the Breast Cancer Association Consortium (BCAC) to evaluate the hypothesis that tumor characteristics modify the association between breast cancer risk and the low penetrant susceptibility loci recently identified <xref rid="pgen.1000054-Easton1" ref-type="bibr">[6]</xref>. Determining whether breast cancer risk factors are linked to tumors with specific clinical presentations, pathologic characteristics or mechanisms of development may provide a gateway for developing tailored prevention and early detection strategies. In addition, we evaluated whether these genetic factors affect overall survival after diagnosis of breast cancer, either independently or through their association with tumor characteristics of clinical importance.</p></sec><sec id="s2"><title>Materials and Methods</title><sec id="s2a"><title>Study Populations</title><p>Cases and controls were identified through 21 case-control studies in Europe, North America, South-East Asia and Australia, participating in the BCAC (see <xref ref-type="supplementary-material" rid="pgen.1000054.s004">Table S1</xref> for description of study populations). All of these studies, except for two Germany studies (Mammary Carcinoma Risk Factor Investogation (MARIE), Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC)), were included in our previous publication <xref rid="pgen.1000054-Easton1" ref-type="bibr">[6]</xref> (the ORIGO study was previously referred to as LUMCBCS), and provided information on disease status, age at diagnosis/enrollment, ethnic group (European, Asian, other), first degree family history of breast cancer and bilaterality of breast cancer. Twenty studies with a total of 23,839 invasive breast cancer cases and 26,928 controls also provided data on tumor characteristics (i.e. histopathologic subtype, ER and PR receptor status, tumor size, grade, nodal involvement or stage; see <xref ref-type="supplementary-material" rid="pgen.1000054.s005">Table S2</xref> for data sources). Of these, 800 cases and 655 controls were excluded from analyses because of failures in genotyping quality control (see details under <italic>Genotyping</italic>) or because they belonged to “other” ethnic groups with few subjects. Data on survival after diagnosis was available for 13,527 cases participating in 13 studies (after excluding failures in genotype QC and “other” ethnicities), including the USRT study, which lacked data on tumor characteristics (<xref ref-type="supplementary-material" rid="pgen.1000054.s007">Table S4</xref>). Overall, 95.6% of cases and 96.7% of controls were of European origin. The mean ages were 56 years for cases and 57 years for controls.</p><p>The distribution of tumor characteristics by study among the 23,039 ( = 23839-800) cases from 20 studies with pathology information is shown in <xref ref-type="supplementary-material" rid="pgen.1000054.s007">Table S4</xref>. Data pertaining to the first tumor detected were used for women with bilateral disease. Data related to histological subtype was available for 86% of the cases (18 studies), ER status for 74% (20 studies), PR status for 62% (18 studies), tumor grade of differentiation for 70% (17 studies), nodal involvement for 65% (17 studies), tumor size for 35% (9 studies), and stage at diagnosis for 68% (11 studies). A total of 1,487 of the 23,039 cases were excluded because they had missing information on all tumor characteristics, leaving 21,552 cases and 26,273 controls of European or Asian origin available for analyses by tumor characteristics. The actual number of cases and controls included in each analysis, after excluding missing genotype data, is shown in the tables.</p></sec><sec id="s2b"><title>Genotyping</title><p>Genotyping procedures have previously been described <xref rid="pgen.1000054-Easton1" ref-type="bibr">[6]</xref>. All studies genotyped for the five SNPs with the exception of rs3803662 that was not genotyped in the KConFab study, and rs13281615 that was not genotyped in KConFab and MARIE studies. Any sample that could not be scored on 20 percent of the SNPs attempted was excluded from analysis. We also removed data for any center/SNP combination for which the call rate was less than 90 percent. In any instances where the call rate was 90–95 percent, the clustering of genotype calls was re-evaluated by an independent observer to determine whether the clustering was sufficiently clear for inclusion. We also eliminated all of the data for a given SNP/center where the reproducibility in duplicate samples was <97 percent, or where there was marked deviation from Hardy-Weinberg equilibrium in the controls (p<.00001).</p></sec><sec id="s2c"><title>Statistical Analyses</title><p>Polytomous logistic regression was used to estimate adjusted odds ratios (OR) and associated 95 percent confidence intervals (CI) as measures of association between genotypes and risk of breast cancer subtypes (comparing case subtypes to all controls). All models included terms for study (dummy variables). Further adjustment for age at diagnosis/enrollment did not substantially influence OR estimates (data not shown). We estimated the association for each SNP in terms of genotype-specific ORs and per-allele ORs (assuming a log-additive model). Heterogeneity between genotype odds ratios for different tumor subtypes was assessed using logistic regression analyses restricted to cases (case-only analyses) with the tumor characteristic as the outcome variable. For tumor subtypes with more than two levels (i.e. grade, size, stage), we used a polytomous logistic regression model constraining the effect size to increase linearly across levels (e.g. the parameter for grade 3 vs grade1 = 2*grade2 vs grade1). To evaluate which of several correlated tumor features was most important in determining genotype associations, we fitted logistic regression models with one of the tumor features as the outcome and the genotype and other tumor features as explanatory variables.</p><p>Survival analyses were based on 13,527 breast cancer cases from 13 studies with available follow-up data. Univariate analyses for each SNP were carried out by estimating Kaplan-Meier survival curves stratified by genotypes, and by fitting Cox proportional hazards regression models adjusting for study and left-truncating at date of blood draw to allow for inclusion of prevalent cases. This provides an unbiased estimate of the hazard ratio provided that the proportional hazards assumption holds. The assumption of proportional hazards was tested by visual inspection of standard log-log plots and analytically using Schoenfeld residuals. Time at risk was calculated from the date of blood sample draw to date of death or last follow-up, whichever date came first. Follow-up for all cases was censored at 10 years after the initial diagnosis because the number of cases with longer time of follow-up was relatively small, and they are likely to be a selected group of patients due to lost to follow up. A total of 1,584 deaths occurred during eligible follow-up. We also carried out analyses adjusting for other determinants of survival (age at diagnosis (continuous), ER and PR status (each dichotomous), grade (ordinal), tumor size (continuous) and nodal involvement (dichotomous)). Survival analyses were conducted for all cases combined, and separately for ER-positive and ER-negative cases. Data were analyzed using STATA v.9. for Windows (College Station, TX).</p><p>The main conclusions from our analyses are based on comparisons of five SNPs with seven correlated tumor characteristics (i.e. ER, PR, grade, nodes, size, histology and stage at diagnosis) and survival after diagnosis. We have used a permutation adjustment procedure <xref rid="pgen.1000054-Westfall1" ref-type="bibr">[21]</xref> to correct P values for these 40 hypothesis tests. The tumor characteristics were permuted in a group with respect to the SNPs. In this procedure, the outcomes (i.e. tumor characteristics) were randomly assigned against the SNPs while retaining the correlation structure of the outcomes. We performed 1000 permutations to obtain the empirical distribution of P values under the null hypothesis of no association. Multiple-comparisons-permutation-adjusted P values for each of the 40 tests were calculated as the proportion of P values equal or smaller than the observed P value.</p></sec><sec id="s2d"><title>Entrez Gene Accession Numbers</title><p><italic>GFR2</italic>: 2263</p><p><italic>TNRC9</italic> or <italic>TOX3</italic>: 27324</p><p><italic>MAP3K1</italic>: 4214</p><p><italic>MIER3</italic>: 166968</p><p><italic>LSP1</italic>: 4046</p><p><italic>v-myc myelocytomatosis viral oncogene homolog (avian) (MYC)</italic>: 4609</p></sec></sec><sec id="s3"><title>Results</title><sec id="s3a"><title>Association between SNPs and Breast Cancer Risk by Tumor Subtypes</title><p>Minor allele frequencies and estimates for the association between the five SNPs evaluated and overall breast cancer risk are shown in <xref ref-type="supplementary-material" rid="pgen.1000054.s008">Table S5</xref>. Stratification of tumors by ER status indicated that rs2981582 in <italic>FGFR2</italic> had a stronger association with ER-positive (per-allele OR (95% CI) = 1.31 (1.27–1.36)) than ER-negative tumors (1.08 (1.03–1.14); P for heterogeneity of ORs = 10<sup>−13</sup>; <xref ref-type="table" rid="pgen-1000054-t001">Table 1</xref>; <xref ref-type="fig" rid="pgen-1000054-g001">Figure 1</xref> panel A; see <xref ref-type="supplementary-material" rid="pgen.1000054.s009">Table S6</xref> for estimates by ethnicity). Women with the homozygous variant genotype (present in 14% of controls) had a risk of ER-positive tumors 1.74 (95%CI = 1.63–1.85) times higher than those with the common homozygous genotype (present in 39% of controls) (<xref ref-type="table" rid="pgen-1000054-t001">Table 1</xref>). The difference in ORs between ER-positive and ER-negative tumors is consistent across studies (<xref ref-type="fig" rid="pgen-1000054-g001">Figure 1</xref> panel A), and it is highly significant even after permutation adjustment for multiple comparisons (P<0.001). The rs2981582 association was also stronger for other tumor characteristics associated with ER status, i.e. PR expression (P = 10<sup>−5</sup>) and lower grade (P = 10<sup>−8</sup>; <xref ref-type="table" rid="pgen-1000054-t002">Table 2</xref>; <xref ref-type="supplementary-material" rid="pgen.1000054.s010">Tables S7</xref>, <xref ref-type="supplementary-material" rid="pgen.1000054.s011">S8</xref>). The associations of rs2981582 with ER, PR and grade were significant after permutation adjustment for multiple comparisons (P≤0.001). The modification by ER status remained statistically significant after adjustment for PR status and grade (P = 0.002) based on data from those studies with information on all three tumor characteristics (16 studies including 10,951 cases). On the other hand, the evidence for associations with PR status became non-significant after adjustment for ER status (P = 0.45). The association with grade (<xref ref-type="table" rid="pgen-1000054-t002">Table 2</xref>) remained statistically significant after adjustment by ER status (P = 0.003), and after further adjustment for PR status (P = 0.030). Grouping tumors as ER and PR negative versus ER and/or PR positive tumors did not result in further discrimination of risks (data not shown).</p><fig id="pgen-1000054-g001" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1000054.g001</object-id><label>Figure 1</label><caption><title>Per-allele odds ratios (ORs) and 95% confidence intervals (CIs) for the association between <italic>FGFR2</italic> (rs2981582) and breast cancer by study.</title><p>A. stratified by ER status, B. stratified by axillary node involvement. Studies are weighted and ranked according to the inverse of the variance of the log OR estimate for ER-positive (A) or node positive (B) tumors. P for study heterogeneity were 0.84 and 0.96, for the association with ER-positive and negative disease, respectively; and 0.64 and 0.97 for node positive and negative diseases, respectively. See <xref ref-type="supplementary-material" rid="pgen.1000054.s004">Table S1</xref> for description of the studies and acronyms.</p></caption><graphic xlink:href="pgen.1000054.g001"></graphic></fig><table-wrap id="pgen-1000054-t001" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1000054.t001</object-id><label>Table 1</label><caption><title>Per-allele odds ratios for breast cancer risk by estrogen receptor status.</title></caption><alternatives><graphic id="pgen-1000054-t001-1" xlink:href="pgen.1000054.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Locus</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">ER-positive cases</td><td colspan="3" align="left" rowspan="1">ER-negative cases</td><td align="left" rowspan="1" colspan="1">Observed</td><td align="left" rowspan="1" colspan="1">Adjusted</td></tr><tr><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">Genotype</td><td align="left" rowspan="1" colspan="1">Controls</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt101">*</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt101">*</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">P<xref ref-type="table-fn" rid="nt102">**</xref></td><td align="left" rowspan="1" colspan="1">P<xref ref-type="table-fn" rid="nt103">***</xref></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">10,056</td><td align="left" rowspan="1" colspan="1">4,043</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1,378</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">12,255</td><td align="left" rowspan="1" colspan="1">6,390</td><td align="left" rowspan="1" colspan="1">1.28</td><td align="left" rowspan="1" colspan="1">1.22–1.35</td><td align="left" rowspan="1" colspan="1">1,828</td><td align="left" rowspan="1" colspan="1">1.08</td><td align="left" rowspan="1" colspan="1">1.00–1.16</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">3,747</td><td align="left" rowspan="1" colspan="1">2,636</td><td align="left" rowspan="1" colspan="1">1.74</td><td align="left" rowspan="1" colspan="1">1.63–1.85</td><td align="left" rowspan="1" colspan="1">607</td><td align="left" rowspan="1" colspan="1">1.18</td><td align="left" rowspan="1" colspan="1">1.06–1.30</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.31</td><td align="left" rowspan="1" colspan="1">1.27–1.36</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.08</td><td align="left" rowspan="1" colspan="1">1.03–1.14</td><td align="left" rowspan="1" colspan="1">10<sup>−13</sup></td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>TNRC9</italic></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">13,295</td><td align="left" rowspan="1" colspan="1">5,970</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1,789</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">9,705</td><td align="left" rowspan="1" colspan="1">5,553</td><td align="left" rowspan="1" colspan="1">1.25</td><td align="left" rowspan="1" colspan="1">1.19–1.31</td><td align="left" rowspan="1" colspan="1">1,579</td><td align="left" rowspan="1" colspan="1">1.16</td><td align="left" rowspan="1" colspan="1">1.08–1.25</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">2,026</td><td align="left" rowspan="1" colspan="1">1,451</td><td align="left" rowspan="1" colspan="1">1.48</td><td align="left" rowspan="1" colspan="1">1.37–1.60</td><td align="left" rowspan="1" colspan="1">397</td><td align="left" rowspan="1" colspan="1">1.28</td><td align="left" rowspan="1" colspan="1">1.13–1.45</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.23</td><td align="left" rowspan="1" colspan="1">1.19–1.27</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.14</td><td align="left" rowspan="1" colspan="1">1.09–1.21</td><td align="left" rowspan="1" colspan="1">0.015</td><td align="left" rowspan="1" colspan="1">0.43</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">TT</td><td align="left" rowspan="1" colspan="1">13,447</td><td align="left" rowspan="1" colspan="1">6,352</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1,912</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">GT</td><td align="left" rowspan="1" colspan="1">10,480</td><td align="left" rowspan="1" colspan="1">5,474</td><td align="left" rowspan="1" colspan="1">1.12</td><td align="left" rowspan="1" colspan="1">1.07–1.17</td><td align="left" rowspan="1" colspan="1">1,539</td><td align="left" rowspan="1" colspan="1">1.03</td><td align="left" rowspan="1" colspan="1">0.96–1.11</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">2,154</td><td align="left" rowspan="1" colspan="1">1,271</td><td align="left" rowspan="1" colspan="1">1.26</td><td align="left" rowspan="1" colspan="1">1.17–1.36</td><td align="left" rowspan="1" colspan="1">370</td><td align="left" rowspan="1" colspan="1">1.20</td><td align="left" rowspan="1" colspan="1">1.06–1.36</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.12</td><td align="left" rowspan="1" colspan="1">1.09–1.16</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.07</td><td align="left" rowspan="1" colspan="1">1.01–1.13</td><td align="left" rowspan="1" colspan="1">0.11</td><td align="left" rowspan="1" colspan="1">0.99</td></tr><tr><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">7,650</td><td align="left" rowspan="1" colspan="1">3,721</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1,158</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">10,682</td><td align="left" rowspan="1" colspan="1">5,681</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.06–1.17</td><td align="left" rowspan="1" colspan="1">1,603</td><td align="left" rowspan="1" colspan="1">0.99</td><td align="left" rowspan="1" colspan="1">0.91–1.07</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">3,773</td><td align="left" rowspan="1" colspan="1">2,298</td><td align="left" rowspan="1" colspan="1">1.29</td><td align="left" rowspan="1" colspan="1">1.21–1.38</td><td align="left" rowspan="1" colspan="1">623</td><td align="left" rowspan="1" colspan="1">1.09</td><td align="left" rowspan="1" colspan="1">0.98–1.21</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.13</td><td align="left" rowspan="1" colspan="1">1.10–1.17</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.03</td><td align="left" rowspan="1" colspan="1">0.98–1.09</td><td align="left" rowspan="1" colspan="1">0.001</td><td align="left" rowspan="1" colspan="1">0.038</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">12,695</td><td align="left" rowspan="1" colspan="1">6,304</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1,867</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs381798</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">10,995</td><td align="left" rowspan="1" colspan="1">5,485</td><td align="left" rowspan="1" colspan="1">1.04</td><td align="left" rowspan="1" colspan="1">0.99–1.09</td><td align="left" rowspan="1" colspan="1">1,587</td><td align="left" rowspan="1" colspan="1">1.01</td><td align="left" rowspan="1" colspan="1">0.94–1.09</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">2,322</td><td align="left" rowspan="1" colspan="1">1,281</td><td align="left" rowspan="1" colspan="1">1.19</td><td align="left" rowspan="1" colspan="1">1.10–1.28</td><td align="left" rowspan="1" colspan="1">363</td><td align="left" rowspan="1" colspan="1">1.13</td><td align="left" rowspan="1" colspan="1">1.00–1.27</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.07</td><td align="left" rowspan="1" colspan="1">1.04–1.11</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.04</td><td align="left" rowspan="1" colspan="1">0.99–1.10</td><td align="left" rowspan="1" colspan="1">0.31</td><td align="left" rowspan="1" colspan="1">1.00</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><p><bold>*:</bold> ORs adjusted for study.</p></fn><fn id="nt102"><p><bold>**:</bold> P for heterogeneity calculated from case-only analyses adjusted for study.</p></fn><fn id="nt103"><p><bold>***:</bold> Permutation adjusted P for heterogeneity</p></fn></table-wrap-foot></table-wrap><table-wrap id="pgen-1000054-t002" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1000054.t002</object-id><label>Table 2</label><caption><title>Odds ratios for breast cancer risk by tumor grade<xref ref-type="table-fn" rid="nt104">*</xref>.</title></caption><alternatives><graphic id="pgen-1000054-t002-2" xlink:href="pgen.1000054.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Locus</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">Grade 1</td><td colspan="3" align="left" rowspan="1">Grade 2</td><td colspan="3" align="left" rowspan="1">Grade 3</td><td align="left" rowspan="1" colspan="1">Obs.</td><td align="left" rowspan="1" colspan="1">Adj.</td></tr><tr><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">Genotype</td><td align="left" rowspan="1" colspan="1">Controls</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt105">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt105">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt105">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">P<xref ref-type="table-fn" rid="nt106">***</xref></td><td align="left" rowspan="1" colspan="1">P<xref ref-type="table-fn" rid="nt107">****</xref></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">8916</td><td align="left" rowspan="1" colspan="1">979</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2368</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1686</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">10988</td><td align="left" rowspan="1" colspan="1">1627</td><td align="left" rowspan="1" colspan="1">1.32</td><td align="left" rowspan="1" colspan="1">1.21–1.43</td><td align="left" rowspan="1" colspan="1">3879</td><td align="left" rowspan="1" colspan="1">1.31</td><td align="left" rowspan="1" colspan="1">1.24–1.39</td><td align="left" rowspan="1" colspan="1">2344</td><td align="left" rowspan="1" colspan="1">1.12</td><td align="left" rowspan="1" colspan="1">1.04–1.20</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">3389</td><td align="left" rowspan="1" colspan="1">696</td><td align="left" rowspan="1" colspan="1">1.83</td><td align="left" rowspan="1" colspan="1">1.64–2.03</td><td align="left" rowspan="1" colspan="1">1521</td><td align="left" rowspan="1" colspan="1">1.68</td><td align="left" rowspan="1" colspan="1">1.55–1.81</td><td align="left" rowspan="1" colspan="1">853</td><td align="left" rowspan="1" colspan="1">1.32</td><td align="left" rowspan="1" colspan="1">1.20–1.44</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.35</td><td align="left" rowspan="1" colspan="1">1.28–1.42</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.30</td><td align="left" rowspan="1" colspan="1">1.25–1.35</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.14</td><td align="left" rowspan="1" colspan="1">1.09–1.19</td><td align="left" rowspan="1" colspan="1">10<sup>−8</sup></td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>TNRC9</italic></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">12073</td><td align="left" rowspan="1" colspan="1">1497</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3620</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2382</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">8570</td><td align="left" rowspan="1" colspan="1">1436</td><td align="left" rowspan="1" colspan="1">1.31</td><td align="left" rowspan="1" colspan="1">1.21–1.42</td><td align="left" rowspan="1" colspan="1">3285</td><td align="left" rowspan="1" colspan="1">1.26</td><td align="left" rowspan="1" colspan="1">1.19–1.33</td><td align="left" rowspan="1" colspan="1">1978</td><td align="left" rowspan="1" colspan="1">1.15</td><td align="left" rowspan="1" colspan="1">1.08–1.23</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">1648</td><td align="left" rowspan="1" colspan="1">340</td><td align="left" rowspan="1" colspan="1">1.49</td><td align="left" rowspan="1" colspan="1">1.31–1.70</td><td align="left" rowspan="1" colspan="1">775</td><td align="left" rowspan="1" colspan="1">1.45</td><td align="left" rowspan="1" colspan="1">1.32–1.59</td><td align="left" rowspan="1" colspan="1">471</td><td align="left" rowspan="1" colspan="1">1.33</td><td align="left" rowspan="1" colspan="1">1.19–1.49</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.25</td><td align="left" rowspan="1" colspan="1">1.19–1.33</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.22</td><td align="left" rowspan="1" colspan="1">1.18–1.27</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.16</td><td align="left" rowspan="1" colspan="1">1.10–1.21</td><td align="left" rowspan="1" colspan="1">0.018</td><td align="left" rowspan="1" colspan="1">0.50</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">TT</td><td align="left" rowspan="1" colspan="1">12218</td><td align="left" rowspan="1" colspan="1">1650</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3890</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2478</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">GT</td><td align="left" rowspan="1" colspan="1">9316</td><td align="left" rowspan="1" colspan="1">1371</td><td align="left" rowspan="1" colspan="1">1.12</td><td align="left" rowspan="1" colspan="1">1.04–1.21</td><td align="left" rowspan="1" colspan="1">3217</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.05–1.17</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">1.07</td><td align="left" rowspan="1" colspan="1">1.00–1.15</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">1767</td><td align="left" rowspan="1" colspan="1">267</td><td align="left" rowspan="1" colspan="1">1.18</td><td align="left" rowspan="1" colspan="1">1.03–1.36</td><td align="left" rowspan="1" colspan="1">679</td><td align="left" rowspan="1" colspan="1">1.26</td><td align="left" rowspan="1" colspan="1">1.15–1.39</td><td align="left" rowspan="1" colspan="1">429</td><td align="left" rowspan="1" colspan="1">1.23</td><td align="left" rowspan="1" colspan="1">1.09–1.38</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.10</td><td align="left" rowspan="1" colspan="1">1.04–1.17</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.12</td><td align="left" rowspan="1" colspan="1">1.07–1.16</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.09</td><td align="left" rowspan="1" colspan="1">1.04–1.15</td><td align="left" rowspan="1" colspan="1">0.91</td><td align="left" rowspan="1" colspan="1">1.00</td></tr><tr><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">6794</td><td align="left" rowspan="1" colspan="1">940</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2163</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1505</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">9335</td><td align="left" rowspan="1" colspan="1">1456</td><td align="left" rowspan="1" colspan="1">1.15</td><td align="left" rowspan="1" colspan="1">1.05–1.26</td><td align="left" rowspan="1" colspan="1">3266</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.04–1.18</td><td align="left" rowspan="1" colspan="1">2063</td><td align="left" rowspan="1" colspan="1">1.01</td><td align="left" rowspan="1" colspan="1">0.94–1.09</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">3185</td><td align="left" rowspan="1" colspan="1">593</td><td align="left" rowspan="1" colspan="1">1.42</td><td align="left" rowspan="1" colspan="1">1.27–1.59</td><td align="left" rowspan="1" colspan="1">1329</td><td align="left" rowspan="1" colspan="1">1.35</td><td align="left" rowspan="1" colspan="1">1.25–1.47</td><td align="left" rowspan="1" colspan="1">783</td><td align="left" rowspan="1" colspan="1">1.14</td><td align="left" rowspan="1" colspan="1">1.03–1.26</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.18</td><td align="left" rowspan="1" colspan="1">1.12–1.25</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.16</td><td align="left" rowspan="1" colspan="1">1.11–1.20</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.06</td><td align="left" rowspan="1" colspan="1">1.01–1.11</td><td align="left" rowspan="1" colspan="1">10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">0.016</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">11239</td><td align="left" rowspan="1" colspan="1">1549</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3669</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2287</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs381798</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">9923</td><td align="left" rowspan="1" colspan="1">1409</td><td align="left" rowspan="1" colspan="1">1.07</td><td align="left" rowspan="1" colspan="1">0.99–1.16</td><td align="left" rowspan="1" colspan="1">3314</td><td align="left" rowspan="1" colspan="1">1.04</td><td align="left" rowspan="1" colspan="1">0.99–1.10</td><td align="left" rowspan="1" colspan="1">2145</td><td align="left" rowspan="1" colspan="1">1.09</td><td align="left" rowspan="1" colspan="1">1.02–1.16</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">2100</td><td align="left" rowspan="1" colspan="1">333</td><td align="left" rowspan="1" colspan="1">1.24</td><td align="left" rowspan="1" colspan="1">1.09–1.41</td><td align="left" rowspan="1" colspan="1">792</td><td align="left" rowspan="1" colspan="1">1.21</td><td align="left" rowspan="1" colspan="1">1.10–1.32</td><td align="left" rowspan="1" colspan="1">476</td><td align="left" rowspan="1" colspan="1">1.17</td><td align="left" rowspan="1" colspan="1">1.04–1.30</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.10</td><td align="left" rowspan="1" colspan="1">1.04–1.16</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.08</td><td align="left" rowspan="1" colspan="1">1.04–1.12</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.08</td><td align="left" rowspan="1" colspan="1">1.03–1.14</td><td align="left" rowspan="1" colspan="1">0.77</td><td align="left" rowspan="1" colspan="1">1.00</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt104"><p><bold>*:</bold> Analyses excluded data from three studies (MEC, NHS and TBCS) without information on tumor grade.</p></fn><fn id="nt105"><p><bold>**:</bold> Per-allele OR adjusted for study.</p></fn><fn id="nt106"><p><bold>***:</bold> P value for heterogeneity of ORs from case-only analyses adjusted by study.</p></fn><fn id="nt107"><p><bold>****:</bold> Permutation adjusted P for heterogeneity</p></fn></table-wrap-foot></table-wrap><p>The association of rs2981582 with breast cancer risk tended to be stronger for patients with positive (per-allele OR (95% CI) = 1.33 (1.27–1.39)) compared to negative (1.25 (1.20–1.29)) nodal involvement (P = 0.013; <xref ref-type="table" rid="pgen-1000054-t003">Table 3</xref>; see <xref ref-type="supplementary-material" rid="pgen.1000054.s012">Table S9</xref> for estimates by ethnicity). Although differences were small and not significant after permutation adjustment for multiple comparisons (P = 0.41), they were consistent across studies (<xref ref-type="fig" rid="pgen-1000054-g001">Figure 1</xref>, panel B). Nodal involvement was correlated with tumor grade and size, and the association between nodal involvement and rs2981582 among cases remained significant (P = 0.010) after adjustment for these tumor characteristics in 9 studies with 6,204 cases. Nodal involvement and ER status were independently associated with rs2981582 in 12,374 cases from 17 studies with data on these two factors (P value for node association with rs2981582 adjusted by ER = 0.022; P = 0.75 after adjusting for multiple testing). rs2981582 showed the strongest association with node positive ER-positive tumors (29% of all tumors; per-allele OR (95% CI) = 1.37 (1.29–1.44)), followed by node negative ER-positive tumors (48% of all tumors; 1.30 (1.25–1.36)) and node positive ER-negative tumors (10% of all tumors; 1.18 (1.09–1.29) (<xref ref-type="supplementary-material" rid="pgen.1000054.s013">Table S10</xref>). No increase in risk was observed for node negative ER-negative tumors (13% of tumors; 1.05 (0.97–1.13).</p><table-wrap id="pgen-1000054-t003" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1000054.t003</object-id><label>Table 3</label><caption><title>Odds ratios for breast cancer risk by lymph node involvement<xref ref-type="table-fn" rid="nt108">*</xref>.</title></caption><alternatives><graphic id="pgen-1000054-t003-3" xlink:href="pgen.1000054.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Locus</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">Cases with negative nodes</td><td colspan="3" align="left" rowspan="1">Cases with positive nodes</td><td align="left" rowspan="1" colspan="1">Observed</td><td align="left" rowspan="1" colspan="1">Adjusted</td></tr><tr><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">Genotype</td><td align="left" rowspan="1" colspan="1">Controls</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt109">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">N</td><td align="left" rowspan="1" colspan="1">OR<xref ref-type="table-fn" rid="nt109">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">P<xref ref-type="table-fn" rid="nt110">***</xref></td><td align="left" rowspan="1" colspan="1">P<xref ref-type="table-fn" rid="nt111">****</xref></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">7494</td><td align="left" rowspan="1" colspan="1">3031</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1683</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">9021</td><td align="left" rowspan="1" colspan="1">4539</td><td align="left" rowspan="1" colspan="1">1.23</td><td align="left" rowspan="1" colspan="1">1.16–1.30</td><td align="left" rowspan="1" colspan="1">2753</td><td align="left" rowspan="1" colspan="1">1.32</td><td align="left" rowspan="1" colspan="1">1.23–1.42</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">2746</td><td align="left" rowspan="1" colspan="1">1734</td><td align="left" rowspan="1" colspan="1">1.56</td><td align="left" rowspan="1" colspan="1">1.44–1.68</td><td align="left" rowspan="1" colspan="1">1104</td><td align="left" rowspan="1" colspan="1">1.77</td><td align="left" rowspan="1" colspan="1">1.61–1.94</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.25</td><td align="left" rowspan="1" colspan="1">1.20–1.29</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.33</td><td align="left" rowspan="1" colspan="1">1.27–1.39</td><td align="left" rowspan="1" colspan="1">0.013</td><td align="left" rowspan="1" colspan="1">0.41</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>TNRC9</italic></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">9762</td><td align="left" rowspan="1" colspan="1">4234</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2470</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">7180</td><td align="left" rowspan="1" colspan="1">3930</td><td align="left" rowspan="1" colspan="1">1.22</td><td align="left" rowspan="1" colspan="1">1.16–1.29</td><td align="left" rowspan="1" colspan="1">2391</td><td align="left" rowspan="1" colspan="1">1.26</td><td align="left" rowspan="1" colspan="1">1.18–1.34</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">1551</td><td align="left" rowspan="1" colspan="1">1028</td><td align="left" rowspan="1" colspan="1">1.36</td><td align="left" rowspan="1" colspan="1">1.24–1.49</td><td align="left" rowspan="1" colspan="1">639</td><td align="left" rowspan="1" colspan="1">1.35</td><td align="left" rowspan="1" colspan="1">1.21–1.51</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.19</td><td align="left" rowspan="1" colspan="1">1.14–1.24</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.20</td><td align="left" rowspan="1" colspan="1">1.14–1.26</td><td align="left" rowspan="1" colspan="1">0.78</td><td align="left" rowspan="1" colspan="1">1.00</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">TT</td><td align="left" rowspan="1" colspan="1">9867</td><td align="left" rowspan="1" colspan="1">4547</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2707</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">GT</td><td align="left" rowspan="1" colspan="1">7753</td><td align="left" rowspan="1" colspan="1">3864</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.05–1.17</td><td align="left" rowspan="1" colspan="1">2291</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.04–1.19</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">1656</td><td align="left" rowspan="1" colspan="1">919</td><td align="left" rowspan="1" colspan="1">1.23</td><td align="left" rowspan="1" colspan="1">1.12–1.35</td><td align="left" rowspan="1" colspan="1">572</td><td align="left" rowspan="1" colspan="1">1.32</td><td align="left" rowspan="1" colspan="1">1.18–1.48</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.06–1.15</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.14</td><td align="left" rowspan="1" colspan="1">1.08–1.19</td><td align="left" rowspan="1" colspan="1">0.31</td><td align="left" rowspan="1" colspan="1">1.00</td></tr><tr><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">5257</td><td align="left" rowspan="1" colspan="1">2607</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1634</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">7316</td><td align="left" rowspan="1" colspan="1">3921</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.04–1.18</td><td align="left" rowspan="1" colspan="1">2372</td><td align="left" rowspan="1" colspan="1">1.08</td><td align="left" rowspan="1" colspan="1">1.00–1.17</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">2741</td><td align="left" rowspan="1" colspan="1">1635</td><td align="left" rowspan="1" colspan="1">1.23</td><td align="left" rowspan="1" colspan="1">1.13–1.33</td><td align="left" rowspan="1" colspan="1">961</td><td align="left" rowspan="1" colspan="1">1.22</td><td align="left" rowspan="1" colspan="1">1.11–1.35</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.07–1.15</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.10</td><td align="left" rowspan="1" colspan="1">1.05–1.16</td><td align="left" rowspan="1" colspan="1">0.95</td><td align="left" rowspan="1" colspan="1">1.00</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">AA</td><td align="left" rowspan="1" colspan="1">9357</td><td align="left" rowspan="1" colspan="1">4531</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2708</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs381798</td><td align="left" rowspan="1" colspan="1">AG</td><td align="left" rowspan="1" colspan="1">8148</td><td align="left" rowspan="1" colspan="1">3917</td><td align="left" rowspan="1" colspan="1">1.03</td><td align="left" rowspan="1" colspan="1">0.98–1.09</td><td align="left" rowspan="1" colspan="1">2318</td><td align="left" rowspan="1" colspan="1">1.05</td><td align="left" rowspan="1" colspan="1">0.98–1.12</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">GG</td><td align="left" rowspan="1" colspan="1">1749</td><td align="left" rowspan="1" colspan="1">866</td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">1.02–1.22</td><td align="left" rowspan="1" colspan="1">534</td><td align="left" rowspan="1" colspan="1">1.20</td><td align="left" rowspan="1" colspan="1">1.07–1.34</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><italic>per allele</italic></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.05</td><td align="left" rowspan="1" colspan="1">1.01–1.09</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.08</td><td align="left" rowspan="1" colspan="1">1.03–1.13</td><td align="left" rowspan="1" colspan="1">0.38</td><td align="left" rowspan="1" colspan="1">1.00</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt108"><p><bold>*:</bold> Analyses excluded data from three studies (GESBC, MCBCS and SEARCH) without information on node involvement.</p></fn><fn id="nt109"><p><bold>**:</bold> Per-allele OR adjusted for study.</p></fn><fn id="nt110"><p><bold>***:</bold> P value for heterogeneity of ORs from case-only analyses adjusted by study.</p></fn><fn id="nt111"><p><bold>****:</bold> Permutation adjusted P for heterogeneity.</p></fn></table-wrap-foot></table-wrap><p>The association of rs13281615 in 8q24 with risk was also stronger for ER-positive compared to ER-negative tumors (P = 0.001; <xref ref-type="table" rid="pgen-1000054-t001">Table 1</xref>; <xref ref-type="supplementary-material" rid="pgen.1000054.s001">Figure S1</xref>). This SNP also showed a stronger association with PR-positive than negative tumors (P = 0.011; <xref ref-type="supplementary-material" rid="pgen.1000054.s010">Table S7</xref>) and lower tumor grade (P = 10<sup>−4</sup>; <xref ref-type="supplementary-material" rid="pgen.1000054.s011">Table S8</xref>). Only the associations of rs13281615 with ER and grade, but not with PR, were significant after permutation adjustment for multiple comparisons (P = 0.037, 0.016, 0.35, respectively). The associations with ER and grade were significant after adjustment for each other (P = 0.029 for ER adjusted for grade and 0.035 for grade adjusted for ER in 15 studies with 11,419 cases with data on ER and grade), while the association with PR was not significant after ER adjustment (P = 0.31). The association of rs3803662 in <italic>TNRC9</italic> and breast cancer was also significantly modified by ER status (P = 0.015; <xref ref-type="table" rid="pgen-1000054-t001">Table 1</xref>)) and grade (P = 0.018; <xref ref-type="table" rid="pgen-1000054-t002">Table 2</xref>). However, these differences were not significant after permutation adjustment for multiple comparisons (P = 0.42 for ER, 0.50 for grade), or when adjusted for each other in 16 studies with 13,075 cases with data on ER and grade (P = 0.11 for ER adjusted by grade, and P = 0.37 for grade adjusted by ER).</p><p>Three SNPs (rs2981582 in <italic>FGFR2</italic>, rs3803662 in <italic>TNRC9</italic> and rs889312 in <italic>MAP3K1</italic>) were associated with significant increases in risk of ER-negative tumors (<xref ref-type="table" rid="pgen-1000054-t001">Table 1</xref>), although to a lesser extent than ER-positive tumors. Of these SNPs, rs3803662 showed the strongest association with ER-negative tumors: women with the homozygous variant genotype (present in 8% of controls) had a 1.28 (95%CI = 1.13–1.45) higher risk of developing ER-negative disease than women with the common homozygous genotype (present in 53% of controls) (<xref ref-type="table" rid="pgen-1000054-t001">Table 1</xref>).</p><p>No significant modification of the ORs was observed for stage at initial diagnosis for any of the 5 loci (<xref ref-type="supplementary-material" rid="pgen.1000054.s016">Table S13</xref>). Of note, rs889312 in <italic>MAP3K1</italic> and rs3817198 in <italic>LSP1</italic> were not associated with any of the tumor characteristics (<xref ref-type="supplementary-material" rid="pgen.1000054.s009">Tables S6</xref>, <xref ref-type="supplementary-material" rid="pgen.1000054.s010">S7</xref>, <xref ref-type="supplementary-material" rid="pgen.1000054.s011">S8</xref>, <xref ref-type="supplementary-material" rid="pgen.1000054.s012">S9</xref> and <xref ref-type="supplementary-material" rid="pgen.1000054.s014">S11</xref>, <xref ref-type="supplementary-material" rid="pgen.1000054.s015">S12</xref>, <xref ref-type="supplementary-material" rid="pgen.1000054.s016">S13</xref>). Modification of ORs by tumor characteristics generally followed similar patterns for Europeans and Asians, although the number of Asians was substantially smaller, and thus most differences by tumor type were not statistically significant. An exception was the presence of stronger associations with larger tumors for rs889312 in <italic>MAP3K1</italic> (P = 0.015; <xref ref-type="supplementary-material" rid="pgen.1000054.s014">Table S11</xref>) in Asian but not in European populations.</p></sec><sec id="s3b"><title>Survival Analyses</title><p>The average time at risk (i.e. date of blood sample draw to date of death, last follow-up or censored time, whichever date came first) among 13,527 breast cancer patients in 13 studies was 6.0 years with a range between <1 and 10 years in individual studies. Cases were followed-up for a total of 54,716 person-years with the occurrence of 1,515 deaths from any cause (<xref ref-type="supplementary-material" rid="pgen.1000054.s006">Table S3</xref>). As expected, survival was poorer for patients with ER negative, PR negative, higher grade and larger tumors and in patients with positive nodes (<xref ref-type="supplementary-material" rid="pgen.1000054.s002">Figure S2</xref>). No differences in survival by genotype were found, except for possibly better survival in patients with the variant allele in rs13281615 at 8q24 (unadjusted per-allele HR (95%CI) = 0.90 (0.83–0.97), P = 0.009; <xref ref-type="table" rid="pgen-1000054-t004">Table 4</xref>). This association was no longer significant after adjustment for ER status, grade and age at diagnosis (adjusted HR = 0.92 (0.83–1.01), <xref ref-type="table" rid="pgen-1000054-t004">Table 4</xref>). Weaker evidence of poorer survival was observed in patients diagnosed with ER-negative tumors carrying the variant allele in rs3803662 (P = 0.071). This association was independent of grade and age at diagnosis (adjusted per-allele HR (95%CI) = 1.19 (0.98–1.44); <xref ref-type="table" rid="pgen-1000054-t004">Table 4</xref>; <xref ref-type="supplementary-material" rid="pgen.1000054.s003">Figure S3</xref>).</p><table-wrap id="pgen-1000054-t004" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1000054.t004</object-id><label>Table 4</label><caption><title>Multivariate Cox proportional hazards analysis of genetic polymorphisms in relation to overall survival following breast cancer diagnosis, by ER status<xref ref-type="table-fn" rid="nt112">*</xref>.</title></caption><alternatives><graphic id="pgen-1000054-t004-4" xlink:href="pgen.1000054.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">Unadjusted<xref ref-type="table-fn" rid="nt113">**</xref></td><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">Adjusted<xref ref-type="table-fn" rid="nt115">****</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Locus</td><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">HR<xref ref-type="table-fn" rid="nt113">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">Obs P</td><td align="left" rowspan="1" colspan="1">Adj P<xref ref-type="table-fn" rid="nt114">***</xref></td><td align="left" rowspan="1" colspan="1">HR<xref ref-type="table-fn" rid="nt113">**</xref></td><td align="left" rowspan="1" colspan="1">95% CI</td><td align="left" rowspan="1" colspan="1">Obs P</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">All tumors</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">0.98</td><td align="left" rowspan="1" colspan="1">0.91–1.05</td><td align="left" rowspan="1" colspan="1">0.56</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">1.01</td><td align="left" rowspan="1" colspan="1">0.92–1.11</td><td align="left" rowspan="1" colspan="1">0.82</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>TNRC9</italic></td><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">1.05</td><td align="left" rowspan="1" colspan="1">0.96–1.15</td><td align="left" rowspan="1" colspan="1">0.26</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">1.06</td><td align="left" rowspan="1" colspan="1">0.95–1.19</td><td align="left" rowspan="1" colspan="1">0.31</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">1.02</td><td align="left" rowspan="1" colspan="1">0.95–1.11</td><td align="left" rowspan="1" colspan="1">0.54</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">1.03</td><td align="left" rowspan="1" colspan="1">0.93–1.15</td><td align="left" rowspan="1" colspan="1">0.52</td></tr><tr><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">0.90</td><td align="left" rowspan="1" colspan="1">0.83–0.97</td><td align="left" rowspan="1" colspan="1">0.009</td><td align="left" rowspan="1" colspan="1">0.32</td><td align="left" rowspan="1" colspan="1">0.92</td><td align="left" rowspan="1" colspan="1">0.83–1.01</td><td align="left" rowspan="1" colspan="1">0.084</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">rs381798</td><td align="left" rowspan="1" colspan="1">0.99</td><td align="left" rowspan="1" colspan="1">0.92–1.07</td><td align="left" rowspan="1" colspan="1">0.88</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">1.03</td><td align="left" rowspan="1" colspan="1">0.93–1.14</td><td align="left" rowspan="1" colspan="1">0.55</td></tr><tr><td colspan="2" align="left" rowspan="1">ER positive tumors</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">0.90–1.11</td><td align="left" rowspan="1" colspan="1">0.98</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.03</td><td align="left" rowspan="1" colspan="1">0.92–1.16</td><td align="left" rowspan="1" colspan="1">0.62</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>TNRC9</italic></td><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">1.02</td><td align="left" rowspan="1" colspan="1">0.89–1.16</td><td align="left" rowspan="1" colspan="1">0.82</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">0.86–1.15</td><td align="left" rowspan="1" colspan="1">0.97</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">0.99</td><td align="left" rowspan="1" colspan="1">0.88–1.11</td><td align="left" rowspan="1" colspan="1">0.82</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.99</td><td align="left" rowspan="1" colspan="1">0.87–1.13</td><td align="left" rowspan="1" colspan="1">0.91</td></tr><tr><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">0.88</td><td align="left" rowspan="1" colspan="1">0.78–0.99</td><td align="left" rowspan="1" colspan="1">0.039</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.89</td><td align="left" rowspan="1" colspan="1">0.78–1.01</td><td align="left" rowspan="1" colspan="1">0.068</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">rs381798</td><td align="left" rowspan="1" colspan="1">1.09</td><td align="left" rowspan="1" colspan="1">0.98–1.23</td><td align="left" rowspan="1" colspan="1">0.12</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.07</td><td align="left" rowspan="1" colspan="1">0.94–1.21</td><td align="left" rowspan="1" colspan="1">0.32</td></tr><tr><td colspan="2" align="left" rowspan="1">ER negative tumors</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">0.99</td><td align="left" rowspan="1" colspan="1">0.85–1.15</td><td align="left" rowspan="1" colspan="1">0.87</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.98</td><td align="left" rowspan="1" colspan="1">0.84–1.14</td><td align="left" rowspan="1" colspan="1">0.78</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>TNRC9</italic></td><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">1.19</td><td align="left" rowspan="1" colspan="1">0.99–1.43</td><td align="left" rowspan="1" colspan="1">0.071</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.19</td><td align="left" rowspan="1" colspan="1">0.98–1.44</td><td align="left" rowspan="1" colspan="1">0.076</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">1.15</td><td align="left" rowspan="1" colspan="1">0.98–1.35</td><td align="left" rowspan="1" colspan="1">0.08</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">0.94–1.32</td><td align="left" rowspan="1" colspan="1">0.22</td></tr><tr><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">0.95</td><td align="left" rowspan="1" colspan="1">0.81–1.11</td><td align="left" rowspan="1" colspan="1">0.48</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.96</td><td align="left" rowspan="1" colspan="1">0.82–1.13</td><td align="left" rowspan="1" colspan="1">0.64</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">rs381798</td><td align="left" rowspan="1" colspan="1">0.95</td><td align="left" rowspan="1" colspan="1">0.81–1.11</td><td align="left" rowspan="1" colspan="1">0.49</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">0.97</td><td align="left" rowspan="1" colspan="1">0.82–1.15</td><td align="left" rowspan="1" colspan="1">0.74</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt112"><p><bold>*:</bold> Analyses by ER status included data from 12 studies with information on vital status and ER status (CGPS, CNIO-BCS, HABCS, HEBCS, KBCP, kConFab, LUMCBCS, MCCS, PBCS, SASBCS, SBCS, SEARCH).</p></fn><fn id="nt113"><p><bold>**:</bold> Per-allele hazard ratios (HR) and observed P values are adjusted for study. Allele changes are (common>rare based on frequencies in European populations): G>A for rs2981582; G>A for rs3803662; T>G for rs889312; A>G for rs13281615 and A>G for rs381798.</p></fn><fn id="nt114"><p><bold>***:</bold> Permutation adjusted P values.</p></fn><fn id="nt115"><p><bold>****:</bold> Per-allele hazard ratios (HR) and observed P values are adjusted for study, age at diagnosis (continuous), ER status and grade (continuous). Analyses limited to 11 studies with ER and grade information (CGPS, CNIO-BCS, HABCS, HEBCS, KBCP, LUMCBCS, MCCS, PBCS, SASBCS, SBCS, SEARCH).</p></fn><fn id="nt116"><label></label><p>The P values for the interaction between ER status and genotype adjusted for study, grade and age at diagnosis are: 0.60, 0.15, 0.29, 0.45, 0.38 for rs2981582, rs3803662, rs889312, rs13281615, rs381798, respectively.</p></fn></table-wrap-foot></table-wrap></sec></sec><sec id="s4"><title>Discussion</title><p>This report has demonstrated that common genetic variants that predispose to breast cancer may also be linked to clinically important characteristics of tumors, including size, grade, ER and PR status, and nodal involvement. A major strength of our study is the large sample size after pooling data from multiple studies with information on tumor characteristics, which allowed for precise estimates of relative risk by most tumor subtypes.</p><p>The most notable finding was for rs2981582 located in <italic>FGFR2</italic>, which showed a stronger association with ER-positive than ER-negative tumors (P = 10<sup>−13</sup>), with lower than higher grade tumors (P = 10<sup>−8</sup>) and with node positive than negative tumors (P = 0.013). This SNP was significantly associated only with ER-negative tumors that involved lymph nodes. rs2981582 also showed stronger associations with PR-positive tumors but this association was not independent of ER status. The stronger association with ER-positive tumors is supported by previous observations indicating that <italic>FGFR2</italic> is involved in estrogen-related breast carcinogenesis <xref rid="pgen.1000054-Zhang1" ref-type="bibr">[22]</xref>–<xref rid="pgen.1000054-Tamaru1" ref-type="bibr">[25]</xref>, and that levels of expression of the receptor are higher in ER-positive than ER-negative cell lines <xref rid="pgen.1000054-Zang1" ref-type="bibr">[26]</xref> and tumors <xref rid="pgen.1000054-Luqmani1" ref-type="bibr">[27]</xref>.</p><p>We have shown previously that the causative variant in <italic>FGFR2</italic> is likely to be one of six variants correlated with rs2981582 in a region of intron 2 containing multiple transcription factor binding sites. This suggests that the association with breast cancer risk may be mediated through differential levels of <italic>FGFR2</italic> expression <xref rid="pgen.1000054-Easton1" ref-type="bibr">[6]</xref>. In addition, as <italic>FGFR2</italic> has been shown to be overexpressed or amplified only in a small percentage of breast cancers <xref rid="pgen.1000054-Heiskanen1" ref-type="bibr">[9]</xref>,<xref rid="pgen.1000054-Adnane1" ref-type="bibr">[10]</xref>,<xref rid="pgen.1000054-Hishikawa1" ref-type="bibr">[24]</xref>, it is possible that the association with breast cancer risk could be stronger and more clinically relevant for the small subset of tumors that express high levels of the receptor. Epidemiological studies stratifying by levels of tumor expression of <italic>FGFR2</italic> , its ligands or co-factors may clarify the role of <italic>FGFR2</italic> variation in breast cancer risk.</p><p>rs13281615 in 8q24 was also more strongly associated with ER-positive and lower grade tumors, although differences were smaller than for rs2981582 in <italic>FGFR2</italic>. Other independent variants in the 8q24 region which does not contain known genes, have been associated with prostate cancer risk <xref rid="pgen.1000054-Gudmundsson1" ref-type="bibr">[11]</xref>,<xref rid="pgen.1000054-Yeager1" ref-type="bibr">[13]</xref>,<xref rid="pgen.1000054-Haiman1" ref-type="bibr">[14]</xref>; however, the mechanisms for the associations with these cancers are unknown. A recent GWAS comprising five studies with 4,533 cases and 17,513 controls (including samples from the MEC study in this report) showed the risk from rs3803662 in <italic>TNRC9</italic> to be significantly greater in ER-positive tumors <xref rid="pgen.1000054-Stacey1" ref-type="bibr">[20]</xref>. Our data also showed a stronger association with ER-positive than ER-negative tumors, but the difference was smaller and not statistically significant based on the analysis of 12,832 cases and 22,356 controls from 18 studies. Moreover, this SNP showed the strongest association with ER-negative disease among the five evaluated. Future studies might reveal stronger associations between these SNPs and tumor subtypes defined by different markers, or perhaps molecular subtypes previously defined by gene expression profiling <xref rid="pgen.1000054-Sorlie2" ref-type="bibr">[28]</xref>,<xref rid="pgen.1000054-vanVeer1" ref-type="bibr">[29]</xref>.</p><p>It is possible that our study preferentially detected SNPs associated with ER-positive rather than ER-negative disease, since the majority of breast cancer cases in the initial GWAS were ER positive. This raises the possibility that genome-wide association studies focusing on the less common breast tumor subtypes may identify different risk loci. Of particular importance might be SNPs identified in studies of basal tumor subtypes since they are often clinically aggressive and difficult to treat effectively, and have been associated with germline mutations in <italic>BRCA1</italic><xref rid="pgen.1000054-Sorlie1" ref-type="bibr">[5]</xref>,<xref rid="pgen.1000054-Sorlie2" ref-type="bibr">[28]</xref>.</p><p>Differences in the design, source of information on tumor characteristics and criteria to classify tumors across studies could lead to heterogeneity of findings by study, which limits the ability to detect modification of genotype associations by tumor characteristics. However, findings were generally consistent across studies (<xref ref-type="fig" rid="pgen-1000054-g001">Figure 1</xref> and <xref ref-type="supplementary-material" rid="pgen.1000054.s001">Figure S1</xref>), particularly for the <italic>FGFR2</italic> (rs2981582) association by ER status, arguing for the robustness of our results. Genotype associations with risk of breast cancer were similar for subjects with and without information on tumor characteristics (data not shown), indicating that missing information is unlikely to substantially affect our results.</p><p>None of the five SNPs included in this report had a significant association with overall survival independent of their associations with known prognostic factors. Only rs13281615 in 8q24 was significantly associated with survival in unadjusted analyses. Adjustment for ER status and grade resulted in a weaker, non-significant association with survival, suggesting that the increased survival is partially mediated through the higher probability of developing tumors with favorable prognostic characteristics. Any SNP effect on overall survival, if mediated through known prognostic tumor characteristics, would be expected to be small because of the small magnitude of risk differences by tumor subtypes; thus the power to detect a difference in survival would be low. For instance, at a type I error rate of 0.01, the power to detect alleles with minor allele frequency (MAF) = 0.3 that confer a per-allele HR of 1.1 is only 40%. Another limitation of the survival analyses is that relapse or disease-specific mortality data were not available for most studies and use of all cause mortality as the end point may further reduce power. Finally, any impact of SNPs on survival may interact with treatment, particularly adjuvant chemotherapy, or other determinants of survival such obesity. However, this could not be evaluated since information on treatment or other factors affecting survival was not available.</p><p>We have shown that there is heterogeneity in the risk of different tumor types for common breast cancer susceptibility alleles, with the clearest difference being in the relative risk of ER-positive and ER-negative tumors for the variant in <italic>FGRF2</italic>. Other differences were observed, however, the weight of evidence was weaker and needs further confirmation in additional studies. These findings provide further support for the notion that ER-negative and ER-positive tumors result from different etiologic pathways, rather than different stages of tumor evolution within a common carcinogenic pathway <xref rid="pgen.1000054-Allred1" ref-type="bibr">[30]</xref>. The magnitude of the observed differences is small, and by themselves these findings are unlikely to have any immediate clinical implications. However, the observed differences provide clues to the biological mechanisms that underpin tumor heterogeneity, which may ultimately lead to improved treatment and prevention.</p></sec><sec sec-type="supplementary-material" id="s5"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pgen.1000054.s001"><label>Figure S1</label><caption><p>Per-allele odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and breast cancer by study, stratified by ER status. Studies are weighted and ranked according to the inverse of the variance of the log OR estimate for ER-positive tumors. P for study heterogeneity for the association with ER-positive/ER-negative disease, respectively, were 0.77/0.99 for rs3803662; 0.72/0.29 rs889312; 0.55/0.31 for rs13281615; and 0.55/0.46 for rs3817198. See <xref ref-type="supplementary-material" rid="pgen.1000054.s004">Table S1</xref> for description of the studies and acronyms.</p><p>(0.30 MB DOC)</p></caption><media xlink:href="pgen.1000054.s001.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s002"><label>Figure S2</label><caption><p>Kaplan-Meier plot showing survival after stratifying for estrogen and progesterone receptor status, histological grade, tumor size, nodal status, and histopathology.</p><p>(0.15 MB DOC)</p></caption><media xlink:href="pgen.1000054.s002.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s003"><label>Figure S3</label><caption><p>Kaplan-Meier plots showing survival in different genotypes of (A.) rs3803662 inTNRC9 and (B.) rs13281615 in 8q24 among cases diagnosed with ER-positive and ER-negative tumors.</p><p>(0.14 MB DOC)</p></caption><media xlink:href="pgen.1000054.s003.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s004"><label>Table S1</label><caption><p>Summary of the 21 breast cancer case studies used in the analyses for tumor characteristics and survival.</p><p>(0.13 MB DOC)</p></caption><media xlink:href="pgen.1000054.s004.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s005"><label>Table S2</label><caption><p>Information content, sources of information for tumor characteristics and survival data, and relevant publications for the 21 participating studies.</p><p>(0.08 MB DOC)</p></caption><media xlink:href="pgen.1000054.s005.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s006"><label>Table S3</label><caption><p>Number of cases, person-years at risk, number of deaths, mortality rate (MR), and 95 percent confidence intervals (95%CI) in the 13 studies with follow-up information.</p><p>(0.05 MB DOC)</p></caption><media xlink:href="pgen.1000054.s006.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s007"><label>Table S4</label><caption><p>Distribution of tumor characteristics among 23,039 invasive breast cancer cases in the 20 participating studies with information on tumor.</p><p>(0.03 MB DOC)</p></caption><media xlink:href="pgen.1000054.s007.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s008"><label>Table S5</label><caption><p>Per-allele odds ratios for the association between SNPs and invasive breast cancer risk in 20 studies included in the assessment of tumor characteristics in this report.</p><p>(0.05 MB DOC)</p></caption><media xlink:href="pgen.1000054.s008.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s009"><label>Table S6</label><caption><p>Per-allele odds ratios for breast cancer risk by estrogen receptor status, stratified by ethnicity.</p><p>(0.07 MB DOC)</p></caption><media xlink:href="pgen.1000054.s009.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s010"><label>Table S7</label><caption><p>Per-allele odds ratios for breast cancer risk by progesterone receptor status, stratified by ethnicity.</p><p>(0.07 MB DOC)</p></caption><media xlink:href="pgen.1000054.s010.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s011"><label>Table S8</label><caption><p>Per-allele odds ratios for breast cancer risk by grade, stratified by ethnicity.</p><p>(0.07 MB DOC)</p></caption><media xlink:href="pgen.1000054.s011.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s012"><label>Table S9</label><caption><p>Per-allele odds ratios for breast cancer risk by nodal status, stratified by ethnicity.</p><p>(0.07 MB DOC)</p></caption><media xlink:href="pgen.1000054.s012.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s013"><label>Table S10</label><caption><p>Per-allele odds ratios for the association between <italic>FGFR2</italic> rs2981582 and breast cancer risk by ER and nodal status.</p><p>(0.03 MB DOC)</p></caption><media xlink:href="pgen.1000054.s013.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s014"><label>Table S11</label><caption><p>Per-allele odds ratios for breast cancer risk by tumor size, stratified by ethnicity.</p><p>(0.09 MB DOC)</p></caption><media xlink:href="pgen.1000054.s014.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s015"><label>Table S12</label><caption><p>Per-allele odds ratios for breast cancer risk by histopathogic subtypes, stratified by ethnicity.</p><p>(0.06 MB DOC)</p></caption><media xlink:href="pgen.1000054.s015.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1000054.s016"><label>Table S13</label><caption><p>Per-allele odds ratios for breast cancer risk by stage at diagnosis, stratified by ethnicity.</p><p>(0.08 MB DOC)</p></caption><media xlink:href="pgen.1000054.s016.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We would like to thank to Guillermo Pita, JM San Roman and the Instituto Palacios for their contributions to this study. We thank Marcia Brumm and Kathleen Merkle for sample and data collection. 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 for their contributions to this resource, and the many families who contribute to kConFab. For Australian Breast Cancer Family Study control data, we thank John Hopper, Margaret McCredie, Graham Giles and Melissa Southey, and for Australian Ovarian Cancer Study control data, we thank the AOCS Management group of David Bowtell, Adele Green, Penny Webb, Dorota Gertig, and Anna deFaxio. We would like to thank Helen Cramp, Sue Higham, Dan Connley, Ian Brock, Gordon Macpherson and Mark Meuth for their contributions to this study. The ORIGO team wishes to thank E. Krol-Warmerdam and J. Blom for data-management and patient-inclusion. We thank Ursula Eilber and Belinda Kaspereit for excellent technical support. We wish to thank patients participating in this study, and Drs. Hannaleena Eerola and Päivi Heikkilä for their help in sample and data collection. We are thankful to Helena Kemiläinen, Aija Parkkinen and Kirsi Alisalo for their contribution to Kuopio Breast Cancer Project. The authors thank N. Szeszenia-Dabrowska of the Nofer Institute of Occupational Medicine and W. Zatonski of the Department of Cancer Epidemiology and Prevention, Cancer Center and M. Sklodowska-Curie Institute of Oncology, 02-781 Warsaw, Poland for their contribution to the Polish Breast Cancer Study. Finnish Cancer Registry is gratefully acknowledged for cancer data. Apart from the general thanking of all study participants, we thank the SEARCH team and the Eastern Registration and Cancer Intelligence Unit. We thank William Anderson from the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA, for his comments to the paper.</p></ack><fn-group><fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="financial-disclosure"><p>This work was funded by The Copenhagen Breast Cancer Study and The Copenhagen General Population Study were supported by Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, Copenhagen County and Herlev University Hospital. The CNIO Spanish Breast Cancer Study was supported by the Genome Spain Foundation and the Marato Foundation. The GENICA study was supported by the German Human Genome Project and funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114. Genotyping analyses were supported by Robert Bosch Foundation of Medical Research, Stuttgart, Germany. The Mayo Breast Cancer Study is supported by NIH/NCI Breast Cancer SPORE P50 CA116201, NIH R01 CA122340 and the U.S. Army Medical Research and Materiel Command breast cancer IDEA award W81XWH-04-1-0588. The kConFab Clinical Follow Up Study is funded by NHMRC grants 145684 and 288704. 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. GCT and ABS are NHMRC Senior Principal Research Fellow and Career Award Development awardees respectively. The Sheffield Breast Cancer Study was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. The RBCS was supported by the Dutch Cancer Genomics Center (CGC). The MARIE study is supported by the Deutsche Krebshilfe e.V. (Project number 70-2892-Br I). Ellen L. Goode was supported by a Fraternal Order of Eagles Cancer Research Fellowship. The Singapore and Swedish Breast Cancer Study (SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. KBCP is supported by grants from EVO funds of Kuopio University Hospital and the Finnish Cancer Foundation. The USRT study was supported by Intramural Research Funds from the Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS. The Polish Breast Cancer Study was funded by Intramural Research Funds of the US National Cancer Institute. HEBCS was supported by the Academy of Finland (110663), Finnish Cancer Society, Helsinki University Central Hospital Research Fund, and the Sigrid Juselius Fund. 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