Rare germline variants in cancer-relevant genes are associated with breast cancer risk in young women with high-risk family history.

Abstract

It is incompletely understood why some women develop breast cancer 15-20years earlier than the majority of women. We hypothesize that women with early-onset breast cancer and high-risk family history without germline pathogenic variants in cancer-predisposing genes (CPGs, n = 83) have a higher load of germline high functional impact variants (gHFI) in cancer hallmark genes (n = 1508) compared to healthy controls. Germline whole exome sequencing data were analyzed from 5818 breast cancer cases from UKBiobank and from 94 young women with breast cancer without CPG pathogenic variants from the Yale Cancer Prevention Clinic, and compared to 149 controls from Yale GENERATIONS project and 56,917 controls from UKBiobank. Rare gHFI variants were compared between cases and controls using the burden test and the optimal unified SNP-set Kernel Association Test (SKAT-O). We assessed germline versus somatic origins of pathway level alterations in the TCGA and Yale data. In UKBiobank, higher gHFI variant load was seen in CPGs in cancer cases regardless of family history (p < 8.78 × 10-8), and in hallmark genes in cases with family history vs controls (p = 0.0093). Similarly, numerically higher rare gHFI burden was seen in hallmark genes in the Yale cohort vs controls, but this difference was not statistically significant. Pathway level alterations were dominated by somatic events. These results suggest that rare germline variants in cancer biology-related genes partly mediate the contribution of family history to cancer risk in individuals without germline alterations in high penetrance CPGs.