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1. Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Author

Gaudet, Mia M., primary, Kirchhoff, Tomas, additional, Green, Todd, additional, Vijai, Joseph, additional, Korn, Joshua M., additional, Guiducci, Candace, additional, Segrè, Ayellet V., additional, McGee, Kate, additional, McGuffog, Lesley, additional, Kartsonaki, Christiana, additional, Morrison, Jonathan, additional, Healey, Sue, additional, Sinilnikova, Olga M., additional, Stoppa-Lyonnet, Dominique, additional, Mazoyer, Sylvie, additional, Gauthier-Villars, Marion, additional, Sobol, Hagay, additional, Longy, Michel, additional, Frenay, Marc, additional, GEMO Study Collaborators, Frans B. L., additional, Rookus, Matti A., additional, Collée, J. Margriet, additional, Hoogerbrugge, Nicoline, additional, van Roozendaal, Kees E. P., additional, Piedmonte, Marion, additional, Rubinstein, Wendy, additional, Nerenstone, Stacy, additional, Van Le, Linda, additional, Blank, Stephanie V., additional, Caldés, Trinidad, additional, de la Hoya, Miguel, additional, Nevanlinna, Heli, additional, Aittomäki, Kristiina, additional, Lazaro, Conxi, additional, Blanco, Ignacio, additional, Arason, Adalgeir, additional, Johannsson, Oskar T., additional, Barkardottir, Rosa B., additional, Devilee, Peter, additional, Olopade, Olofunmilayo I., additional, Neuhausen, Susan L., additional, Wang, Xianshu, additional, Fredericksen, Zachary S., additional, Peterlongo, Paolo, additional, Manoukian, Siranoush, additional, Barile, Monica, additional, Viel, Alessandra, additional, Radice, Paolo, additional, Phelan, Catherine M., additional, Narod, Steven, additional, Rennert, Gad, additional, Lejbkowicz, Flavio, additional, Flugelman, Anath, additional, Andrulis, Irene L., additional, Glendon, Gord, additional, Ozcelik, Hilmi, additional, Toland, Amanda E., additional, Montagna, Marco, additional, D'Andrea, Emma, additional, Friedman, Eitan, additional, Laitman, Yael, additional, Borg, Ake, additional, Beattie, Mary, additional, Ramus, Susan J., additional, Domchek, Susan M., additional, Nathanson, Katherine L., additional, Rebbeck, Tim, additional, Spurdle, Amanda B., additional, Chen, Xiaoqing, additional, Holland, Helene, additional, John, Esther M., additional, Hopper, John L., additional, Buys, Saundra S., additional, Daly, Mary B., additional, Southey, Melissa C., additional, Terry, Mary Beth, additional, Tung, Nadine, additional, Overeem Hansen, Thomas V., additional, Nielsen, Finn C., additional, Greene, Mark H., additional, Mai, Phuong L., additional, Osorio, Ana, additional, Durán, Mercedes, additional, Andres, Raquel, additional, Benítez, Javier, additional, Weitzel, Jeffrey N., additional, Garber, Judy, additional, Hamann, Ute, additional, Peock, Susan, additional, Cook, Margaret, additional, Oliver, Clare, additional, Frost, Debra, additional, Platte, Radka, additional, Evans, D. Gareth, additional, Lalloo, Fiona, additional, Eeles, Ros, additional, Izatt, Louise, additional, Walker, Lisa, additional, Eason, Jacqueline, additional, Barwell, Julian, additional, Godwin, Andrew K., additional, Schmutzler, Rita K., additional, Wappenschmidt, Barbara, additional, Engert, Stefanie, additional, Arnold, Norbert, additional, Gadzicki, Dorothea, additional, Dean, Michael, additional, Gold, Bert, additional, Klein, Robert J., additional, Couch, Fergus J., additional, Chenevix-Trench, Georgia, additional, Easton, Douglas F., additional, Daly, Mark J., additional, Antoniou, Antonis C., additional, Altshuler, David M., additional, and Offit, Kenneth, additional

Published
2010
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2. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Author

Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM, Guiducci C, Segrè AV, McGee K, McGuffog L, Kartsonaki C, Morrison J, Healey S, Sinilnikova OM, Stoppa-Lyonnet D, Mazoyer S, Gauthier-Villars M, Sobol H, Longy M, Frenay M, GEMO Study Collaborators, Hogervorst FB, Rookus MA, Collée JM, Hoogerbrugge N, van Roozendaal KE, Piedmonte M, Rubinstein W, Nerenstone S, Van Le L, Blank SV, Caldés T, de la Hoya M, Nevanlinna H, Aittomäki K, Lazaro C, Blanco I, Arason A, Johannsson OT, Barkardottir RB, Devilee P, Olopade OI, Neuhausen SL, Wang X, Fredericksen ZS, Peterlongo P, Manoukian S, Barile M, Viel A, Radice P, Phelan CM, Narod S, Rennert G, Lejbkowicz F, Flugelman A, Andrulis IL, Glendon G, Ozcelik H, Toland AE, Montagna M, D'Andrea E, Friedman E, Laitman Y, Borg A, Beattie M, Ramus SJ, Domchek SM, Nathanson KL, Rebbeck T, Spurdle AB, Chen X, Holland H, John EM, Hopper JL, Buys SS, Daly MB, Southey MC, Terry MB, Tung N, Overeem Hansen TV, Nielsen FC, Greene MH, Mai PL, Osorio A, Durán M, Andres R, Benítez J, Weitzel JN, Garber J, Hamann U, Peock S, Cook M, Oliver C, Frost D, Platte R, Evans DG, Lalloo F, Eeles R, Izatt L, Walker L, Eason J, Barwell J, Godwin AK, Schmutzler RK, Wappenschmidt B, Engert S, Arnold N, Gadzicki D, Dean M, Gold B, Klein RJ, Couch FJ, Chenevix-Trench G, Easton DF, Daly MJ, Antoniou AC, Altshuler DM, and Offit K

Subjects
Adult, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 20, DNA-Binding Proteins genetics, Female, Gene Frequency, Genetic Predisposition to Disease genetics, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Middle Aged, Mutation, Penetrance, Receptor, Fibroblast Growth Factor, Type 2 genetics, Risk Factors, Transcription Factors genetics, White People genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide
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 (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) 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, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). 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., Competing Interests: The authors have declared that no competing interests exist.

Published
2010
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