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Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Lookup NU author(s): Dr Paul Brennan

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Abstract

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

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Author(s): Barnes DR, Rookus MA, McGuffog L, Leslie G, Mooij TM, Dennis J, Mavaddat N, Adlard J, Ahmed M, Aittomaki K, Andrieu N, Andrulis IL, Arnold N, Arun BK, Azzollini J, Balmana J, Barkardottir RB, Barrowdale D, Benitez J, Berthet P, Bialkowska K, Blanco AM, Blok MJ, Bonanni B, Boonen SE, Borg A, Bozsik A, Bradbury AR, Brennan P, Brewer C, Brunet J, Buys SS, Caldes T, Caligo MA, Campbell I, Christensen LL, Chung WK, Claes KBM, Colas C, Collonge-Rame M-A, Cook J, Daly MB, Davidson R, de la Hoya M, de Putter R, Delnatte C, Devilee P, Diez O, Ding YC, Domchek SM, Dorfling CM, Dumont M, Eeles R, Ejlertsen B, Engel C, Evans DG, Faivre L, Foretova L, Fostira F, Friedlander M, Friedman E, Frost D, Ganz PA, Garber J, Gehrig A, Gerdes A-M, Gesta P, Giraud S, Glendon G, Godwin AK, Goldgar DE, Gonzalez-Neira A, Greene MH, Gschwantler-Kaulich D, Hahnen E, Hamann U, Hanson H, Hentschel J, Hogervorst FBL, Hooning MJ, Horvath J, Hu C, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James PA, Janavicius R, John EM, Joseph V, Karlan BY, Kast K, Koudijs M, Kruse TA, Kwong A, Laitman Y, Lasset C, Lazaro C, Lester J, Lesueur F, Liljegren A, Loud JT, Lubinski J, Mai PL, Manoukian S, Mari V, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller A, Montagna M, Mouret-Fourme E, Mukherjee S, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Niederacher D, Nielsen FC, Nikitina-Zake L, Nogues C, Olah E, Olopade OI, Ong K-R, O'Shaughnessy-Kirwan A, Osorio A, Ott C-E, Papi L, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Peterlongo P, Pfeiler G, Phillips K-A, Prajzendanc K, Pujana MA, Radice P, Ramser J, Ramus SJ, Rantala J, Rennert G, Risch HA, Robson M, Ronlund K, Salani R, Schuster H, Senter L, Shah PD, Sharma P, Side LE, Singer CF, Slavin TP, Soucy P, Southey MC, Spurdle AB, Steinemann D, Steinsnyder Z, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teo SH, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Trainer AH, Tung N, van Engelen K, van Rensburg EJ, Vega A, Vierstraete J, Wagner G, Walker L, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Yadav S, Yang X, Yannoukakos D, Zimbalatti D, Offit K, Thomassen M, Couch FJ, Schmutzler RK, Simard J, Easton DF, Chenevix-Trench G, Antoniou AC

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2020

Volume: 22

Issue: 10

Pages: 1653-1666

Print publication date: 01/10/2020

Online publication date: 15/07/2020

Acceptance date: 29/05/2020

Date deposited: 14/01/2021

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41436-020-0862-x

DOI: 10.1038/s41436-020-0862-x

PubMed id: 32665703

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