@article{TEXTUAL,
      recid = {10882},
      author = {Gaudet, Mia M. and Kirchhoff, Tomas and Green, Todd and  Vijai, Joseph and Korn, Joshua M. and Guiducci, Candace and  Segrè, Ayellet V. and McGee, Kate and McGuffog, Lesley and  Kartsonaki, Christiana and Morrison, Jonathan and Healey,  Sue and Sinilnikova, Olga M. and Stoppa-Lyonnet, Dominique  and Mazoyer, Sylvie and Gauthier-Villars, Marion and Sobol,  Hagay and Frenay, Marc and GEMO Study Collaborators and  Olopade, Olofunmilayo I},
      title = {Common Genetic Variants and Modification of Penetrance of  <i>BRCA2</i>-Associated Breast Cancer},
      journal = {PLOS Genetics},
      address = {2010-10-28},
      number = {TEXTUAL},
      abstract = {<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>},
      url = {http://knowledge.uchicago.edu/record/10882},
}