Breast and Prostate Cancer Risks for MaleBRCA1andBRCA2Pathogenic Variant Carriers Using Polygenic Risk Scores

Abstract

Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.

Breast and prostate cancer risk: The interplay of polygenic risk, rare pathogenic germline variants, and family history

“…30 Another recent work showed that there is a wide-range of absolute risks for breast cancer and prostate cancer in PV heterozygotes in terms of different genes and across PRS stratification. 31 Our results showed that the PRS acts as a risk modifier for breast cancer and prostate cancer among both the general population and PV heterozygotes in all the well-known cancer susceptibility risk genes. PRS can define a significant proportion of the general population that is at a risk comparable with PV heterozygotes for moderate-risk genes or even more when considering family history.…”

Germline genetics of prostate cancer

“…A recent study by Barnes et al 47 used a population‐based polygenic risk score‐based approach to determine risk and found that polygenic risk score for prostate cancer based on a population was associated with higher rates of prostate cancer for BRCA1 carriers and BRCA2 carriers. For BRCA2 carriers by age 85, the 5th and 95th percentile prostate cancer risks were reported as 34.1%– 87.6%, respectively 47 …”

Principles of molecular testing for hereditary cancer

“…PRS for breast, colorectal and prostate cancers in particular may be informative for population-based screening and prevention. 210,[212][213][214][215][216][217][218][219][220] Polygenic background can modify risks for monogenic cancers, and PRS may therefore have utility for refining cancer risk estimates for patients with monogenic cancer variants. 221 For example, the BOADICEA model for breast cancer risk prediction incorporates PRS along with monogenic variants and other risk factors (eg, age, mammographic density) to generate personalized breast cancer risk estimates.…”

“…Polygenic risk scores (PRS) are an emerging tool for cancer risk prediction. The combined effect of many genetic risk variants can be used to construct PRS 212 . PRS may identify a greater proportion of the population at increased risk for cancer than would be identified by traditional genetic testing approaches.…”

“…PRS may identify a greater proportion of the population at increased risk for cancer than would be identified by traditional genetic testing approaches. PRS for breast, colorectal and prostate cancers in particular may be informative for population‐based screening and prevention 210,212–220 . Polygenic background can modify risks for monogenic cancers, and PRS may therefore have utility for refining cancer risk estimates for patients with monogenic cancer variants 221 .…”