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000010882 02470 $$ahttps://doi.org/10.1371/journal.pgen.1001183$$2doi
000010882 037__ $$aTEXTUAL
000010882 037__ $$bArticle
000010882 041__ $$aeng
000010882 245__ $$aCommon Genetic Variants and Modification of Penetrance of <i>BRCA2</i>-Associated Breast Cancer
000010882 269__ $$a2010-10-28
000010882 336__ $$aArticle
000010882 520__ $$a<p>The considerable uncertainty regarding cancer risks associated with inherited mutations of <em>BRCA2</em> is due to unknown factors. To investigate whether common genetic variants modify penetrance for <em>BRCA2</em> mutation carriers, we undertook a two-staged genome-wide association study in <em>BRCA2</em> mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and <em>BRCA2*6174delT</em> mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10<span>−5</span> and 39 SNPs had p-values<10<span>−4</span>. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in <em>ZNF365</em>, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, <em>BRCA2*6174delT</em>. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, <span class="inline-formula"><img class="inline-graphic" src="https://journals.plos.org/plosgenetics/article/file?type=thumbnail&id=10.1371/journal.pgen.1001183.e001" alt="" /></span>) and for rs311499 was 0.72 (95% CI 0.61–0.85, <span class="inline-formula"><img class="inline-graphic" src="https://journals.plos.org/plosgenetics/article/file?type=thumbnail&id=10.1371/journal.pgen.1001183.e002" alt="" /></span>). <em>FGFR2</em> rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, <span class="inline-formula"><img class="inline-graphic" src="https://journals.plos.org/plosgenetics/article/file?type=thumbnail&id=10.1371/journal.pgen.1001183.e003" alt="" /></span>). These results indicate that SNPs that modify <em>BRCA2</em> penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic <em>BRCA2</em> wild-type breast cancer.</p>
000010882 536__ $$oStarr Cancer Research Consortium
000010882 536__ $$oBreast Cancer Research Foundation
000010882 536__ $$1P20CA103694-3$$oNational Institutes of Health
000010882 536__ $$oLymphoma Foundation
000010882 540__ $$a<p>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the <a href="https://creativecommons.org/publicdomain/zero/1.0/" target="_blank">Creative Commons CC0</a> public domain dedication.</p>
000010882 593__ $$aDue to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.
000010882 690__ $$aBiological Sciences Division
000010882 691__ $$aMedicine
000010882 692__ $$aCenter for Clinical Cancer Genetics and Global Health
000010882 7001_ $$aGaudet, Mia M.$$uAlbert Einstein College of Medicine
000010882 7001_ $$aKirchhoff, Tomas$$uMemorial Sloan-Kettering Cancer Center
000010882 7001_ $$aGreen, Todd$$uHarvard University
000010882 7001_ $$aVijai, Joseph$$uMemorial Sloan-Kettering Cancer Center
000010882 7001_ $$aKorn, Joshua M.$$uHarvard University
000010882 7001_ $$aGuiducci, Candace$$uHarvard University
000010882 7001_ $$aSegrè, Ayellet V.$$uMassachusetts General Hospital
000010882 7001_ $$aMcGee, Kate$$uNational Cancer Institute
000010882 7001_ $$aMcGuffog, Lesley$$uUniversity of Cambridge
000010882 7001_ $$aKartsonaki, Christiana$$uUniversity of Cambridge
000010882 7001_ $$aMorrison, Jonathan$$uUniversity of Cambridghe
000010882 7001_ $$aHealey, Sue$$uUniversity of Cambridge
000010882 7001_ $$aSinilnikova, Olga M.$$uUniversité de Lyon
000010882 7001_ $$aStoppa-Lyonnet, Dominique$$uInstitut Curie
000010882 7001_ $$aMazoyer, Sylvie$$uUniversité de Lyon
000010882 7001_ $$aGauthier-Villars, Marion$$uInstitut Curie
000010882 7001_ $$aSobol, Hagay$$uUniversité d'Aix-Marseille II
000010882 7001_ $$aFrenay, Marc$$uInstitut Bergonié
000010882 7001_ $$aGEMO Study Collaborators
000010882 7001_ $$aOlopade, Olofunmilayo I$$uUniversity of Chicago
000010882 773__ $$tPLOS Genetics
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