The Landscape of Somatic Genetic Alterations in Breast Cancers from Germline Mutation Carriers.

Pathogenic germline variants in checkpoint kinase 2 (), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). -associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the wild-type allele. Conversely, -associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. -associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that -associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of -associated BCs. Specific germline variants may have a distinct impact on tumor biology.