Genetic Evolution in BRCA1 ‐Associated Breast Cancer Reveals Early Driver Mutations Shaping Tumor Features and Prognosis

Pathogenic germline variants in the BRCA1 gene significantly increase the lifetime risk of breast cancer and are frequently associated with early‐onset and triple‐negative disease. However, the chronology of genetic events during breast tumor evolution in BRCA1 carriers remains unclear. In this study, 57 primary breast tumors from 57 BRCA1 carriers were analyzed, including formalin‐fixed paraffin‐embedded specimens and fresh‐frozen specimens. Formalin‐fixed paraffin‐embedded tumors were microdissected into normal mammary tissue, carcinoma in situ, and invasive carcinoma components for deep target‐region sequencing, whereas fresh‐frozen tumors underwent whole‐exome sequencing and bulk transcriptome sequencing. Compared with non‐carriers from The Cancer Genome Atlas, breast cancers from BRCA1 carriers showed a distinct mutational landscape characterized by a high prevalence of TP53 mutations and a reduced frequency of PIK3CA and GATA3 alterations. Based on the initiating driver event, BRCA1 ‐associated tumors were classified into three subgroups: TP53 , PI(3)K‐AKT pathway, and unclassified. The TP53 ‐driven subgroup was strongly associated with the triple‐negative phenotype, loss of heterozygosity at the BRCA1 locus, and elevated genomic instability. TP53 truncating mutations were enriched in BRCA1 carriers compared with non‐carriers and showed a trend toward worse outcomes, potentially related to lower homologous recombination deficiency scores and activation of epithelial‐mesenchymal transition pathways. These findings highlight the distinct mutational architecture of breast cancers from BRCA1 carriers and suggest that TP53 truncating mutations may define a particularly aggressive subtype that warrants further investigation.