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Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

Identifieur interne : 000769 ( Ncbi/Curation ); précédent : 000768; suivant : 000770

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

Auteurs : Xianshu Wang ; V. Shane Pankratz [États-Unis] ; Zachary Fredericksen [États-Unis] ; Robert Tarrell [États-Unis] ; Mary Karaus [États-Unis] ; Lesley Mcguffog ; Paul D. P. Pharaoh [Royaume-Uni] ; Bruce A. J. Ponder [Royaume-Uni] ; Alison M. Dunning [Royaume-Uni] ; Susan Peock ; Margaret Cook ; Clare Oliver ; Debra Frost ; Olga M. Sinilnikova [France] ; Dominique Stoppa-Lyonnet [France] ; Sylvie Mazoyer [France] ; Claude Houdayer [France] ; Frans B. L. Hogervorst [Pays-Bas] ; Maartje J. Hooning [Pays-Bas] ; Marjolijn J. Ligtenberg [Pays-Bas] ; Amanda Spurdle [Australie] ; Georgia Chenevix-Trench [Australie] ; Rita K. Schmutzler [Allemagne] ; Barbara Wappenschmidt [Allemagne] ; Christoph Engel [Allemagne] ; Alfons Meindl [Allemagne] ; Susan M. Domchek [États-Unis] ; Katherine L. Nathanson [États-Unis] ; Timothy R. Rebbeck [États-Unis] ; Christian F. Singer [Autriche] ; Daphne Gschwantler-Kaulich [Autriche] ; Catherina Dressler [Autriche] ; Anneliese Fink [Autriche] ; Csilla I. Szabo ; Michal Zikan [République tchèque] ; Lenka Foretova [République tchèque] ; Kathleen Claes [Belgique] ; Gilles Thomas [États-Unis] ; Robert N. Hoover [États-Unis] ; David J. Hunter [États-Unis] ; Stephen J. Chanock [États-Unis] ; Douglas F. Easton ; Antonis C. Antoniou ; Fergus J. Couch [États-Unis]

Source :

RBID : PMC:2893806

Abstract

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 10−3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69–0.90, Ptrend = 3.6 × 10−4 and HR = 1.25, 95% CI: 1.10–1.41, Ptrend = 4.2 × 10−4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25–1.92, Ptrend = 6 × 10−5 and HR = 1.37, 95% CI: 1.16–1.62, Ptrend = 1.7 × 10−4). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.


Url:
DOI: 10.1093/hmg/ddq174
PubMed: 20418484
PubMed Central: 2893806

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PMC:2893806

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Lesley Mcguffog
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<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
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Susan Peock
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<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
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Margaret Cook
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<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
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Clare Oliver
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Debra Frost
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Douglas F. Easton
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Antonis C. Antoniou
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</affiliation>

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<name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M." last="Sinilnikova">Olga M. Sinilnikova</name>
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<country xml:lang="fr">France</country>
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,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<addr-line>Paris</addr-line>
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<country xml:lang="fr">France</country>
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<name sortKey="Hogervorst, Frans B L" sort="Hogervorst, Frans B L" uniqKey="Hogervorst F" first="Frans B. L." last="Hogervorst">Frans B. L. Hogervorst</name>
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<addr-line>Department of Pathology</addr-line>
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<addr-line>Amsterdam</addr-line>
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<country>The Netherlands</country>
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<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<institution>Queensland Institute of Medical Research</institution>
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<addr-line>Brisbane, QLD 4029</addr-line>
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<institution>University Hospital of Cologne</institution>
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<addr-line>Cologne</addr-line>
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<country>Germany</country>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
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<addr-line>Center of Familial Breast and Ovarian Cancer</addr-line>
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<addr-line>Cologne</addr-line>
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<country>Germany</country>
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<institution>University of Leipzig</institution>
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<addr-line>Leipzig</addr-line>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<institution>Technical University</institution>
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<addr-line>Munich</addr-line>
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<country>Germany</country>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Domchek, Susan M" sort="Domchek, Susan M" uniqKey="Domchek S" first="Susan M." last="Domchek">Susan M. Domchek</name>
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<institution>University of Pennsylvania</institution>
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<addr-line>Philadelphia, PA</addr-line>
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<country xml:lang="fr">États-Unis</country>
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<author>
<name sortKey="Nathanson, Katherine L" sort="Nathanson, Katherine L" uniqKey="Nathanson K" first="Katherine L." last="Nathanson">Katherine L. Nathanson</name>
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<nlm:aff id="af16">
<institution>University of Pennsylvania</institution>
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<addr-line>Philadelphia, PA</addr-line>
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<author>
<name sortKey="Rebbeck, Timothy R" sort="Rebbeck, Timothy R" uniqKey="Rebbeck T" first="Timothy R." last="Rebbeck">Timothy R. Rebbeck</name>
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<nlm:aff id="af16">
<institution>University of Pennsylvania</institution>
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<addr-line>Philadelphia, PA</addr-line>
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<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
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<author>
<name sortKey="Singer, Christian F" sort="Singer, Christian F" uniqKey="Singer C" first="Christian F." last="Singer">Christian F. Singer</name>
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<institution>Medical University of Vienna</institution>
,
<addr-line>Vienna</addr-line>
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<country xml:lang="fr">Autriche</country>
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<name sortKey="Gschwantler Kaulich, Daphne" sort="Gschwantler Kaulich, Daphne" uniqKey="Gschwantler Kaulich D" first="Daphne" last="Gschwantler-Kaulich">Daphne Gschwantler-Kaulich</name>
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<addr-line>Vienna</addr-line>
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<nlm:aff id="af17">
<institution>Medical University of Vienna</institution>
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<addr-line>Vienna</addr-line>
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,</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fink, Anneliese" sort="Fink, Anneliese" uniqKey="Fink A" first="Anneliese" last="Fink">Anneliese Fink</name>
<affiliation wicri:level="1">
<nlm:aff id="af17">
<institution>Medical University of Vienna</institution>
,
<addr-line>Vienna</addr-line>
,
<country>Austria</country>
,</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Szabo, Csilla I" sort="Szabo, Csilla I" uniqKey="Szabo C" first="Csilla I." last="Szabo">Csilla I. Szabo</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af1">
<addr-line>Department of Laboratory Medicine and Pathology</addr-line>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Zikan, Michal" sort="Zikan, Michal" uniqKey="Zikan M" first="Michal" last="Zikan">Michal Zikan</name>
<affiliation wicri:level="1">
<nlm:aff id="af18">
<addr-line>Department of Biochemistry and Experimental Oncology, First Faculty of Medicine</addr-line>
,
<institution>Charles University</institution>
,
<addr-line>Prague</addr-line>
,
<country>Czech Republic</country>
,</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Foretova, Lenka" sort="Foretova, Lenka" uniqKey="Foretova L" first="Lenka" last="Foretova">Lenka Foretova</name>
<affiliation wicri:level="1">
<nlm:aff id="af19">
<addr-line>Department of Cancer Epidemiology and Genetics</addr-line>
,
<institution>Masaryk Memorial Cancer Institute</institution>
,
<addr-line>Brno</addr-line>
,
<country>Czech Republic</country>
,</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Claes, Kathleen" sort="Claes, Kathleen" uniqKey="Claes K" first="Kathleen" last="Claes">Kathleen Claes</name>
<affiliation wicri:level="1">
<nlm:aff id="af20">
<addr-line>Center for Medical Genetics</addr-line>
,
<institution>Ghent University Hospital</institution>
,
<addr-line>Ghent</addr-line>
,
<country>Belgium</country>
,</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Thomas, Gilles" sort="Thomas, Gilles" uniqKey="Thomas G" first="Gilles" last="Thomas">Gilles Thomas</name>
<affiliation wicri:level="1">
<nlm:aff id="af21">
<addr-line>Division of Cancer Epidemiology and Genetics</addr-line>
,
<institution>National Cancer Institute, National Institutes of Health</institution>
,
<addr-line>Bethesda, MD</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hoover, Robert N" sort="Hoover, Robert N" uniqKey="Hoover R" first="Robert N." last="Hoover">Robert N. Hoover</name>
<affiliation wicri:level="1">
<nlm:aff id="af21">
<addr-line>Division of Cancer Epidemiology and Genetics</addr-line>
,
<institution>National Cancer Institute, National Institutes of Health</institution>
,
<addr-line>Bethesda, MD</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af22">
<addr-line>Program in Molecular and Genetic Epidemiology</addr-line>
,
<institution>Harvard School of Public Health</institution>
,
<addr-line>Boston, MA</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff wicri:cut=" and" id="af23">
<institution>Brigham and Women's Hospital and Harvard Medical School</institution>
,
<addr-line>Boston, MA</addr-line>
,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af24">
<addr-line>Advanced Technology Center</addr-line>
,
<institution>National Cancer Institute</institution>
,
<addr-line>Gaithersburg, MD</addr-line>
,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Antoniou, Antonis C" sort="Antoniou, Antonis C" uniqKey="Antoniou A" first="Antonis C." last="Antoniou">Antonis C. Antoniou</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af1">
<addr-line>Department of Laboratory Medicine and Pathology</addr-line>
</nlm:aff>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af2">
<addr-line>Health Sciences Research</addr-line>
,
<institution>Mayo Clinic</institution>
,
<addr-line>Rochester, MN</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt>
<idno type="wicri:source">PMC</idno>
<idno type="pmid">20418484</idno>
<idno type="pmc">2893806</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893806</idno>
<idno type="RBID">PMC:2893806</idno>
<idno type="doi">10.1093/hmg/ddq174</idno>
<date when="2010">2010</date>
<idno type="wicri:Area/Pmc/Corpus">001880</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001880</idno>
<idno type="wicri:Area/Pmc/Curation">001739</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001739</idno>
<idno type="wicri:Area/Pmc/Checkpoint">002623</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">002623</idno>
<idno type="wicri:Area/Ncbi/Merge">000769</idno>
<idno type="wicri:Area/Ncbi/Curation">000769</idno>
</publicationStmt>
<sourceDesc>
<biblStruct>
<analytic>
<title xml:lang="en" level="a" type="main">Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers</title>
<author>
<name sortKey="Wang, Xianshu" sort="Wang, Xianshu" uniqKey="Wang X" first="Xianshu" last="Wang">Xianshu Wang</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af1">
<addr-line>Department of Laboratory Medicine and Pathology</addr-line>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Pankratz, V Shane" sort="Pankratz, V Shane" uniqKey="Pankratz V" first="V. Shane" last="Pankratz">V. Shane Pankratz</name>
<affiliation wicri:level="1">
<nlm:aff id="af2">
<addr-line>Health Sciences Research</addr-line>
,
<institution>Mayo Clinic</institution>
,
<addr-line>Rochester, MN</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fredericksen, Zachary" sort="Fredericksen, Zachary" uniqKey="Fredericksen Z" first="Zachary" last="Fredericksen">Zachary Fredericksen</name>
<affiliation wicri:level="1">
<nlm:aff id="af2">
<addr-line>Health Sciences Research</addr-line>
,
<institution>Mayo Clinic</institution>
,
<addr-line>Rochester, MN</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Tarrell, Robert" sort="Tarrell, Robert" uniqKey="Tarrell R" first="Robert" last="Tarrell">Robert Tarrell</name>
<affiliation wicri:level="1">
<nlm:aff id="af2">
<addr-line>Health Sciences Research</addr-line>
,
<institution>Mayo Clinic</institution>
,
<addr-line>Rochester, MN</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Karaus, Mary" sort="Karaus, Mary" uniqKey="Karaus M" first="Mary" last="Karaus">Mary Karaus</name>
<affiliation wicri:level="1">
<nlm:aff id="af2">
<addr-line>Health Sciences Research</addr-line>
,
<institution>Mayo Clinic</institution>
,
<addr-line>Rochester, MN</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcguffog, Lesley" sort="Mcguffog, Lesley" uniqKey="Mcguffog L" first="Lesley" last="Mcguffog">Lesley Mcguffog</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Pharaoh, Paul D P" sort="Pharaoh, Paul D P" uniqKey="Pharaoh P" first="Paul D. P." last="Pharaoh">Paul D. P. Pharaoh</name>
<affiliation wicri:level="1">
<nlm:aff id="af4">
<addr-line>Department of Oncology</addr-line>
,
<institution>University of Cambridge</institution>
,
<addr-line>Cambridge</addr-line>
,
<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af4">
<addr-line>Department of Oncology</addr-line>
,
<institution>University of Cambridge</institution>
,
<addr-line>Cambridge</addr-line>
,
<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dunning, Alison M" sort="Dunning, Alison M" uniqKey="Dunning A" first="Alison M." last="Dunning">Alison M. Dunning</name>
<affiliation wicri:level="1">
<nlm:aff id="af4">
<addr-line>Department of Oncology</addr-line>
,
<institution>University of Cambridge</institution>
,
<addr-line>Cambridge</addr-line>
,
<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Peock, Susan" sort="Peock, Susan" uniqKey="Peock S" first="Susan" last="Peock">Susan Peock</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Cook, Margaret" sort="Cook, Margaret" uniqKey="Cook M" first="Margaret" last="Cook">Margaret Cook</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Oliver, Clare" sort="Oliver, Clare" uniqKey="Oliver C" first="Clare" last="Oliver">Clare Oliver</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Frost, Debra" sort="Frost, Debra" uniqKey="Frost D" first="Debra" last="Frost">Debra Frost</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Sinilnikova, Olga M" sort="Sinilnikova, Olga M" uniqKey="Sinilnikova O" first="Olga M." last="Sinilnikova">Olga M. Sinilnikova</name>
<affiliation wicri:level="1">
<nlm:aff id="af5">
<institution>Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard</institution>
,
<addr-line>Lyon</addr-line>
,
<country>France</country>
,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Stoppa Lyonnet, Dominique" sort="Stoppa Lyonnet, Dominique" uniqKey="Stoppa Lyonnet D" first="Dominique" last="Stoppa-Lyonnet">Dominique Stoppa-Lyonnet</name>
<affiliation wicri:level="1">
<nlm:aff id="af6">
<addr-line>INSERM U509, Service de Génétique Oncologique, Institut Curie</addr-line>
,
<institution>Université Paris-Descartes</institution>
,
<addr-line>Paris</addr-line>
,
<country>France</country>
,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mazoyer, Sylvie" sort="Mazoyer, Sylvie" uniqKey="Mazoyer S" first="Sylvie" last="Mazoyer">Sylvie Mazoyer</name>
<affiliation wicri:level="1">
<nlm:aff id="af7">
<addr-line>Equipe labellisée LIGUE 2008, UMR5201 CNRS</addr-line>
,
<institution>Centre Léon Bérard, Université de Lyon</institution>
,
<addr-line>Lyon</addr-line>
,
<country>France</country>
,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Houdayer, Claude" sort="Houdayer, Claude" uniqKey="Houdayer C" first="Claude" last="Houdayer">Claude Houdayer</name>
<affiliation wicri:level="1">
<nlm:aff id="af6">
<addr-line>INSERM U509, Service de Génétique Oncologique, Institut Curie</addr-line>
,
<institution>Université Paris-Descartes</institution>
,
<addr-line>Paris</addr-line>
,
<country>France</country>
,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hogervorst, Frans B L" sort="Hogervorst, Frans B L" uniqKey="Hogervorst F" first="Frans B. L." last="Hogervorst">Frans B. L. Hogervorst</name>
<affiliation wicri:level="1">
<nlm:aff id="af8">
<addr-line>Department of Pathology</addr-line>
,
<institution>Family Cancer Clinic, The Netherlands Cancer Institute</institution>
,
<addr-line>Amsterdam</addr-line>
,
<country>The Netherlands</country>
,</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af9">
<addr-line>Department of Medical Oncology</addr-line>
,
<institution>Rotterdam Family Cancer Clinic</institution>
,
<addr-line>Erasmus</addr-line>
,
<country>The Netherlands</country>
,</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Ligtenberg, Marjolijn J" sort="Ligtenberg, Marjolijn J" uniqKey="Ligtenberg M" first="Marjolijn J." last="Ligtenberg">Marjolijn J. Ligtenberg</name>
<affiliation wicri:level="1">
<nlm:aff id="af10">
<addr-line>Department of Human Genetics</addr-line>
,
<institution>Radboud University Medical Center</institution>
,
<addr-line>Nijmegen</addr-line>
,
<country>The Netherlands</country>
,</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Spurdle, Amanda" sort="Spurdle, Amanda" uniqKey="Spurdle A" first="Amanda" last="Spurdle">Amanda Spurdle</name>
<affiliation wicri:level="1">
<nlm:aff id="af11">
<institution>Queensland Institute of Medical Research</institution>
,
<addr-line>Brisbane, QLD 4029</addr-line>
,
<country>Australia</country>
,</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af11">
<institution>Queensland Institute of Medical Research</institution>
,
<addr-line>Brisbane, QLD 4029</addr-line>
,
<country>Australia</country>
,</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K." last="Schmutzler">Rita K. Schmutzler</name>
<affiliation wicri:level="1">
<nlm:aff id="af13">
<addr-line>Center of Familial Breast and Ovarian Cancer</addr-line>
,
<institution>University Hospital of Cologne</institution>
,
<addr-line>Cologne</addr-line>
,
<country>Germany</country>
,</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wappenschmidt, Barbara" sort="Wappenschmidt, Barbara" uniqKey="Wappenschmidt B" first="Barbara" last="Wappenschmidt">Barbara Wappenschmidt</name>
<affiliation wicri:level="1">
<nlm:aff id="af13">
<addr-line>Center of Familial Breast and Ovarian Cancer</addr-line>
,
<institution>University Hospital of Cologne</institution>
,
<addr-line>Cologne</addr-line>
,
<country>Germany</country>
,</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Engel, Christoph" sort="Engel, Christoph" uniqKey="Engel C" first="Christoph" last="Engel">Christoph Engel</name>
<affiliation wicri:level="1">
<nlm:aff id="af14">
<addr-line>Institute of Medical Informatics, Statistics and Epidemiology</addr-line>
,
<institution>University of Leipzig</institution>
,
<addr-line>Leipzig</addr-line>
,
<country>Germany</country>
,</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name>
<affiliation wicri:level="1">
<nlm:aff id="af15">
<addr-line>Department of Obstetrics and Gynaecology, Klinikum rechts der Isar</addr-line>
,
<institution>Technical University</institution>
,
<addr-line>Munich</addr-line>
,
<country>Germany</country>
,</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Domchek, Susan M" sort="Domchek, Susan M" uniqKey="Domchek S" first="Susan M." last="Domchek">Susan M. Domchek</name>
<affiliation wicri:level="1">
<nlm:aff id="af16">
<institution>University of Pennsylvania</institution>
,
<addr-line>Philadelphia, PA</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Nathanson, Katherine L" sort="Nathanson, Katherine L" uniqKey="Nathanson K" first="Katherine L." last="Nathanson">Katherine L. Nathanson</name>
<affiliation wicri:level="1">
<nlm:aff id="af16">
<institution>University of Pennsylvania</institution>
,
<addr-line>Philadelphia, PA</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Rebbeck, Timothy R" sort="Rebbeck, Timothy R" uniqKey="Rebbeck T" first="Timothy R." last="Rebbeck">Timothy R. Rebbeck</name>
<affiliation wicri:level="1">
<nlm:aff id="af16">
<institution>University of Pennsylvania</institution>
,
<addr-line>Philadelphia, PA</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Singer, Christian F" sort="Singer, Christian F" uniqKey="Singer C" first="Christian F." last="Singer">Christian F. Singer</name>
<affiliation wicri:level="1">
<nlm:aff id="af17">
<institution>Medical University of Vienna</institution>
,
<addr-line>Vienna</addr-line>
,
<country>Austria</country>
,</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Gschwantler Kaulich, Daphne" sort="Gschwantler Kaulich, Daphne" uniqKey="Gschwantler Kaulich D" first="Daphne" last="Gschwantler-Kaulich">Daphne Gschwantler-Kaulich</name>
<affiliation wicri:level="1">
<nlm:aff id="af17">
<institution>Medical University of Vienna</institution>
,
<addr-line>Vienna</addr-line>
,
<country>Austria</country>
,</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dressler, Catherina" sort="Dressler, Catherina" uniqKey="Dressler C" first="Catherina" last="Dressler">Catherina Dressler</name>
<affiliation wicri:level="1">
<nlm:aff id="af17">
<institution>Medical University of Vienna</institution>
,
<addr-line>Vienna</addr-line>
,
<country>Austria</country>
,</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fink, Anneliese" sort="Fink, Anneliese" uniqKey="Fink A" first="Anneliese" last="Fink">Anneliese Fink</name>
<affiliation wicri:level="1">
<nlm:aff id="af17">
<institution>Medical University of Vienna</institution>
,
<addr-line>Vienna</addr-line>
,
<country>Austria</country>
,</nlm:aff>
<country xml:lang="fr">Autriche</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Szabo, Csilla I" sort="Szabo, Csilla I" uniqKey="Szabo C" first="Csilla I." last="Szabo">Csilla I. Szabo</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af1">
<addr-line>Department of Laboratory Medicine and Pathology</addr-line>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Zikan, Michal" sort="Zikan, Michal" uniqKey="Zikan M" first="Michal" last="Zikan">Michal Zikan</name>
<affiliation wicri:level="1">
<nlm:aff id="af18">
<addr-line>Department of Biochemistry and Experimental Oncology, First Faculty of Medicine</addr-line>
,
<institution>Charles University</institution>
,
<addr-line>Prague</addr-line>
,
<country>Czech Republic</country>
,</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Foretova, Lenka" sort="Foretova, Lenka" uniqKey="Foretova L" first="Lenka" last="Foretova">Lenka Foretova</name>
<affiliation wicri:level="1">
<nlm:aff id="af19">
<addr-line>Department of Cancer Epidemiology and Genetics</addr-line>
,
<institution>Masaryk Memorial Cancer Institute</institution>
,
<addr-line>Brno</addr-line>
,
<country>Czech Republic</country>
,</nlm:aff>
<country xml:lang="fr">République tchèque</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Claes, Kathleen" sort="Claes, Kathleen" uniqKey="Claes K" first="Kathleen" last="Claes">Kathleen Claes</name>
<affiliation wicri:level="1">
<nlm:aff id="af20">
<addr-line>Center for Medical Genetics</addr-line>
,
<institution>Ghent University Hospital</institution>
,
<addr-line>Ghent</addr-line>
,
<country>Belgium</country>
,</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Thomas, Gilles" sort="Thomas, Gilles" uniqKey="Thomas G" first="Gilles" last="Thomas">Gilles Thomas</name>
<affiliation wicri:level="1">
<nlm:aff id="af21">
<addr-line>Division of Cancer Epidemiology and Genetics</addr-line>
,
<institution>National Cancer Institute, National Institutes of Health</institution>
,
<addr-line>Bethesda, MD</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hoover, Robert N" sort="Hoover, Robert N" uniqKey="Hoover R" first="Robert N." last="Hoover">Robert N. Hoover</name>
<affiliation wicri:level="1">
<nlm:aff id="af21">
<addr-line>Division of Cancer Epidemiology and Genetics</addr-line>
,
<institution>National Cancer Institute, National Institutes of Health</institution>
,
<addr-line>Bethesda, MD</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af22">
<addr-line>Program in Molecular and Genetic Epidemiology</addr-line>
,
<institution>Harvard School of Public Health</institution>
,
<addr-line>Boston, MA</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff wicri:cut=" and" id="af23">
<institution>Brigham and Women's Hospital and Harvard Medical School</institution>
,
<addr-line>Boston, MA</addr-line>
,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:level="1">
<nlm:aff id="af24">
<addr-line>Advanced Technology Center</addr-line>
,
<institution>National Cancer Institute</institution>
,
<addr-line>Gaithersburg, MD</addr-line>
,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</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 wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Antoniou, Antonis C" sort="Antoniou, Antonis C" uniqKey="Antoniou A" first="Antonis C." last="Antoniou">Antonis C. Antoniou</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af3">
<addr-line>Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit</addr-line>
</nlm:aff>
<wicri:noCountry code="subfield">Cancer Research UK Genetic Epidemiology Unit</wicri:noCountry>
</affiliation>
</author>
<author>
<name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name>
<affiliation>
<nlm:aff wicri:cut=" and" id="af1">
<addr-line>Department of Laboratory Medicine and Pathology</addr-line>
</nlm:aff>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="af2">
<addr-line>Health Sciences Research</addr-line>
,
<institution>Mayo Clinic</institution>
,
<addr-line>Rochester, MN</addr-line>
,
<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Human Molecular Genetics</title>
<idno type="ISSN">0964-6906</idno>
<idno type="eISSN">1460-2083</idno>
<imprint>
<date when="2010">2010</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in
<italic>BRCA1</italic>
and
<italic>BRCA2</italic>
mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for
<italic>BRCA1</italic>
and
<italic>BRCA2</italic>
may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (
<italic>P</italic>
< 1 × 10
<sup>−3</sup>
) in two breast cancer GWAS studies were genotyped in 3451
<italic>BRCA1</italic>
and 2006
<italic>BRCA2</italic>
mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in
<italic>BRCA1</italic>
carriers and 12 SNPs in
<italic>BRCA2</italic>
carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (
<italic>P</italic>
<sub>trend</sub>
< 0.01). The minor alleles of rs6138178 in
<italic>SNRPB</italic>
and rs6602595 in
<italic>CAMK1D</italic>
displayed the strongest associations in
<italic>BRCA1</italic>
carriers (HR = 0.78, 95% CI: 0.69–0.90,
<italic>P</italic>
<sub>trend</sub>
= 3.6 × 10
<sup>−4</sup>
and HR = 1.25, 95% CI: 1.10–1.41,
<italic>P</italic>
<sub>trend</sub>
= 4.2 × 10
<sup>−4</sup>
), whereas rs9393597 in
<italic>LOC134997</italic>
and rs12652447 in
<italic>FBXL7</italic>
showed the strongest associations in
<italic>BRCA2</italic>
carriers (HR = 1.55, 95% CI: 1.25–1.92,
<italic>P</italic>
<sub>trend</sub>
= 6 × 10
<sup>−5</sup>
and HR = 1.37, 95% CI: 1.16–1.62,
<italic>P</italic>
<sub>trend</sub>
= 1.7 × 10
<sup>−4</sup>
). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in
<italic>BRCA1</italic>
and
<italic>BRCA2</italic>
carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in
<italic>BRCA1</italic>
and
<italic>BRCA2</italic>
carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.</p>
</div>
</front>
</TEI>
</record>

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