Germline variants of the POLH and RAD51 genes are candidate variants associated with risk of hormone receptor-negative young-onset breast cancer.

Only 15% of young-onset breast cancers have identifiable hereditary germline pathogenic variants (PVs) in an established breast cancer susceptibility gene. However, it is believed that a significant proportion of these breast cancers have additional monogenic or rare risk variants that require identification. To uncover novel cancer susceptibility genes, we performed germline whole-exome/genome sequencing of samples from 564 patients with young-onset breast cancer (aged <40 years), as well as samples from 4032 female controls. The identified candidate variants were further genotyped in 6,967 independent breast cancer cases across all age groups. We identified two PVs that were significantly associated with the risk of hormone receptor-negative young-onset breast cancer: POLH p.K589T (OR = 3.65, 95% confidence interval [CI] = 1.28-10.4, P = 0.0095) and RAD51 p.M1fs (OR = 2.15, 95% CI = 1.15-4.02, P = 0.014). When BRCA1/2 PV carriers were excluded from the analysis, only RAD51 p.M1fs retained a significant association. Whole-genome sequencing of tumor samples carrying these germline risk variants revealed that they harbored mutational signatures indicative of a deficiency of homologous recombination. These findings suggest that hereditary POLH p.K589T and RAD51 p.M1fs are candidate variants associated with an increased risk of hormone receptor-negative breast cancer.