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Kuchenbaecker KB, McGuffog L, Barrowdale D, Lee A, Soucy P, Dennis J, Domchek SM, Robson M, Spurdle AB, Ramus SJ, Mavaddat N, Terry MB, Neuhausen SL, Schmutzler RK, Simard J, Pharoah PD, Offit K, Couch FJ, Chenevix-Trench G, Easton DF, Antoniou AC, Lush M, Hamann U, Southey M, John EM, Chung WK, Daly MB, Buys SS, Goldgar DE, Dorfling CM, van Rensburg EJ, Chun Ding Y, Ejlertsen B, Gerdes AM, Hansen TV, Slager S, Hallberg E, Benitez J, Osorio A, Cohen N, Lawler W, Weitzel JN, Peterlongo P, Pensotti V, Dolcetti R, Barile M, Bonanni B, Azzollini J, Manoukian S, Peissel B, Radice P, Savarese A, Papi L, Giannini G, Fostira F, Konstantopoulou I, Adlard J, Brewer C, Cook J, Davidson R, Eccles D, Eeles R, Ellis S, Frost D, Hodgson S, Izatt L, Lalloo F, Ong KR, Godwin AK, Arnold N, Dworniczak B, Engel C, Gehrig A, Hahnen E, Hauke J, Kast K, Meindl A, Niederacher D, Schmutzler RK, Varon-Mateeva R, Wang-Gohrke S, Wappenschmidt B, Barjhoux L, Collonge-Rame MA, Elan C, Golmard L, Barouk-Simonet E, Lesueur F, Mazoyer S, Sokolowska J, Stoppa-Lyonnet D, Isaacs C, Claes KB, Poppe B, de la Hoya M, Garcia-Barberan V, Aittomaki K, Nevanlinna H, Ausems M, de Lange JL, Gomez Garcia EB, Hogervorst FB, Kets CM, Meijers-Heijboer HE, Oosterwijk JC, Rookus MA, van Asperen CJ, van den Ouweland AM, van Doorn HC, van Os TA, Kwong A, Olah E, Diez O, Brunet J, Lazaro C, Teule A, Gronwald J, Jakubowska A, Kaczmarek K, Lubinski J, Sukiennicki G, Barkardottir RB, Chiquette J, Agata S, Montagna M, Teixeira MR, Kyung Park S, Olswold C, Tischkowitz M, Foretova L, Gaddam P, Vijai J, Pfeiler G, Rappaport-Fuerhauser C, Singer CF, Tea MK, Greene MH, Loud JT, Rennert G, Imyanitov EN, Hulick PJ, Hays JL, Piedmonte M, Rodriguez GC, Martyn J, Glendon G, Mulligan AM, Andrulis IL, Toland AE, Jenson UB, Kruse TA, Sokilde Pedersen I, Thomassen M, Caligo MA, Teo SH, Berger R, Friedman E, Laitman Y, Arver B, Borg A, Ehrancrona H, Rantala J, Olopade OI, Ganz PA, Nussbaum RL, Bradbury AR, Domchek SM, Nathanson KL, Arun BK, James P, Karlan BY, Lester J, Simard J, Pharoah PD, Offit K, Couch FJ, Chenevix-Trench G, Easton DF, Antoniou AC
Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers
J Natl Cancer Inst (2017) In process.
Abstract
Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2x10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2x10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
Note
Publication Date: 2017-07-01.
PMCID: PMC5408990
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Last updated on Thursday, November 02, 2017