Gaudet, MM;
Kirchhoff, T;
Green, T;
Vijai, J;
Korn, JM;
Guiducci, C;
Segre, AV;
... kConFab; + view all
(2010)
Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer.
PLOS GENET
, 6
(10)
, Article e1001183. 10.1371/journal.pgen.1001183.
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Abstract
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 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 BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). 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 ZNF365, 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, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
| Type: | Article |
|---|---|
| Title: | Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1001183 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1001183 |
| Language: | English |
| Additional information: | 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. Funding: This study was supported by the Starr Cancer Research Consortium and the Breast Cancer Research Foundation, as well as by NIH NCI: P20CA103694-3 and the Lymphoma Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY GENES, RECURRENT BRCA1, RISK, POPULATION, MODEL, PREDISPOSITION, ASSOCIATION, PHENOTYPE, FREQUENCY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/885132 |
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