Gaudet, MM and Kirchhoff, T and Green, T and Vijai, J and Korn, JM and Guiducci, C and Segre, AV and McGee, K and McGuffog, L and Kartsonaki, C and Morrison, J and Healey, S and Sinilnikova, OM and Stoppa-Lyonnet, D and Mazoyer, S and Gauthier-Villars, M and Sobol, H and Longy, M and Frenay, M and Hogervorst, FBL and Rookus, MA and Collee, JM and Hoogerbrugge, N and van Roozendaal, KEP and Piedmonte, M and Rubinstein, W and Nerenstone, S and Van Le, L and Blank, SV and Caldes, T and de la Hoya, M and Nevanlinna, H and Aittomaki, K and Lazaro, C and Blanco, I and Arason, A and Johannsson, OT and Barkardottir, RB and Devilee, P and Olopade, OI and Neuhausen, SL and Wang, XS and Fredericksen, ZS and Peterlongo, P and Manoukian, S and Barile, M and Viel, A and Radice, P and Phelan, CM and Narod, S and Rennert, G and Lejbkowicz, F and Flugelman, A and Andrulis, IL and Glendon, G and Ozcelik, H and Toland, AE and Montagna, M and D'Andrea, E and Friedman, E and Laitman, Y and Borg, A and Beattie, M and Ramus, SJ and Domchek, SM and Nathanson, KL and Rebbeck, T and Spurdle, AB and Chen, XQ and Holland, H and John, EM and Hopper, JL and Buys, SS and Daly, MB and Southey, MC and Terry, MB and Tung, N and Hansen, TVO and Nielsen, FC and Greene, MI and Mai, PL and Osorio, A and Duran, M and Andres, R and Benitez, J and Weitzel, JN and Garber, J and Hamann, U and Peock, S and Cook, M and Oliver, C and Frost, D and Platte, R and Evans, DG and Lalloo, F and Eeles, R and Izatt, L and Walker, L and Eason, J and Barwell, J and Godwin, AK and Schmutzler, RK and Wappenschmidt, B and Engert, S and Arnold, N and Gadzicki, D and Dean, M and Gold, B and Klein, RJ and Couch, FJ and Chenevix-Trench, G and Easton, DF and Daly, MJ and Antoniou, AC and Altshuler, DM and Offit, K and GEMO Study Collaborators, and HEBON Study Collaborators, and OCGN, and kConFab, (2010) Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer. PLOS GENET , 6 (10) , Article e1001183. 10.1371/journal.pgen.1001183.
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.
|Title:||Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer|
|Open access status:||An open access publication|
|Keywords:||BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY GENES, RECURRENT BRCA1, RISK, POPULATION, MODEL, PREDISPOSITION, ASSOCIATION, PHENOTYPE, FREQUENCY|
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