Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Abstract

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer

“…BRCA1 function‐off‐mutations are well described in development and progression of different solid tumors particularly breast and ovarian cancers but also PCa. Germline BRCA1 mutations are shown to be associated with the higher risk of the onset of PCa and/or more aggressive course of the disease . Of note, BRCA1 dysfunction might be particularly interesting in the context of tumor response to therapy Patients suffering from tumors with BRCA1‐dysfuntion might profit from poly(ADP‐ribose) polymerases (PARP) inhibitor‐based therapies, tested currently in some clinical trials including also patients with PCa in such trials as TOPARP trial (NCT01682772), PROFound study (NCT02987543) and TRITON3 (NCT02975934) .…”

Genetic risk score modifies the effect of APOE on risk and age onset of Alzheimer's disease

“…The phenomenon that GRS modified the effect of major gene ( APOE ) on AD risk and disease onset was similar to the findings in genetic studies of cancer. In a study of 1802 male carriers of BRCA1 / 2 pathogenic mutations, Lecarpentier et al found that the effect of these two major genes on prostate cancer risk was modified by PRS calculated based on 103 prostate cancer risk‐associated SNPs. For example, prostate cancer risk by age 80 years was ~32% among all BRCA2 carriers but was 19% and 61% if their PRS was at the 5th and 95th percentile, respectively.…”

Genetic counseling, 2030: An on‐demand service tailored to the needs of a price conscious, genetically literate, and busy world

“…Counselors will need to conduct comprehension studies to determine the best way to communicate these concepts to clients. Additionally, recent research indicates that PGS can be used to help refine disease risk for individuals with a monogenic predisposition to disease (Lecarpentier et al, ). All previous research about how people react to genetic information may need to be validated and/or updated for this new context.…”