Mutational landscape of normal breast tissues adjacent to invasive breast cancer.

Individuals with a history of breast cancer are at increased risk of developing a new breast cancer during their lifetime. Rare but high-impact somatic mutations in normal breast tissues may contribute to malignant transformation. We analyze mutations in cancer-relevant pathways across matched samples of peripheral blood, cancer-adjacent normal breast, and breast cancer from patients diagnosed before 50 years of age who carry no germline mutations in cancer-predisposing genes. Gene- and pathway-level mutation profiles and single-base substitution (SBS) signatures are compared between tissue types in two independent cohorts (Yale, n = 24; TCGA, n = 17). Cancer-adjacent normal breast tissue contains multiple acquired somatic mutations that persist in tumors. Most variants are shared across tissue types from the same individual, indicating strong germline influence. The substantial germline contribution to alterations through common and rare polymorphisms in cancer hallmark pathways supports a model of cancer risk based on the collective impact of variants in cancer-related genes.