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oai:recercat.cat:11351/64872026-03-26T05:29:27Zcom_2072_378070com_2072_378040col_2072_378092

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants Rookus, Matti A. McGuffog, Lesley Mooij, Thea M. Balmaña Gelpí, Judith Diez Gibert, Orland Barnes, Daniel Dennis, Joe Leslie, Goska Institut Català de la Salut [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Mama - Càncer - Aspectes genètics Ovaris - Càncer - Aspectes genètics Diàtesi DISEASES::Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms PHENOMENA AND PROCESSES::Genetic Phenomena::Genotype::Genetic Predisposition to Disease ENFERMEDADES::neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama FENÓMENOS Y PROCESOS::fenómenos genéticos::genotipo::predisposición genética a la enfermedad BRCA1/2; Càncer de mama; Genètica BRCA1/2; Cáncer de mama; Genética BRCA1/2; Breast cancer; Genetics 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. 2021-10-29T11:47:52Z 2021-10-29T11:47:52Z 2020-10 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Barnes DR, Rookus MA, McGuffog L, Leslie G, Mooij TM, Dennis J, et al. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet Med. 2020 Oct;22(10):1653–66. 1530-0366 https://hdl.handle.net/11351/6487 10.1038/s41436-020-0862-x 32665703 000548481100002 eng Genetics in Medicine;22(10) https://doi.org/10.1038/s41436-020-0862-x Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Springer Nature Scientia