Clinical characteristics and exploratory genomic analyses of germline BRCA1 or BRCA2 mutations in breast cancer.

gBRCA1/2 mutations increase the incidence of breast cancer (BC) by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 BC have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 BC. Sanger sequencing to identify gBRCA1/2 mutations was conducted in 2,720 patients, and gBRCA1 (n=128) and gBRCA2 (n=126) mutations were analyzed. Within that population, deep target sequencing (TS) and matched whole transcriptome sequencing (WTS) results were available for 46 and 34 patients, respectively. An internal database of breast-cancer patients with wild-type gBRCA was used to compile a TS (n=195) and WTS (n=137) reference dataset. Three specific mutation sites, p.Y130X (n=14) and p.1210Afs (n=13) in gBRCA1 and p.R294X (n=22) in gBRCA2, were comparably frequent. Immunohistochemistry subtyping determined that the incidence of triple negative BC was higher among those with a gBRCA1 mutation (71.9%), and estrogen receptor (ER)-positive BC was dominant in those with a gBRCA2 mutation (76.2%). gBRCA1/2 mutations were mutually exclusive with PIK3CA somatic mutations (P<0.05), and gBRCA1 frequently co-occurred with TP53 somatic mutations (P<0.05). The median tumor mutation burden was 6.53 per megabase (MB) in gBRCA1 and 6.44 per MB in gBRCA2. The expression of AR, ESR1, and PGR was significantly upregulated with gBRCA2 mutation compared with gBRCA1 mutation. gBRCA1 and gBRCA2 BC have similar clinical characteristics, but they have different molecular subtypes, co-altered somatic mutations, and gene expression patterns. Implications: Even though gBRCA1 and gBRCA2 mutations both alter HRR pathways, our results suggest that they generate different molecular characteristics and different mechanisms of carcinogenesis.