Genetic risk and clinical implications of BRCA1 and BRCA2 mutations in Turkish triple-negative breast cancer patients

Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Genetic mutations, particularly in BRCA1 and BRCA2, significantly influence its pathogenesis and clinical outcomes. This study evaluated the prevalence of BRCA1 and BRCA2 mutations in Turkish TNBC patients and investigated associated clinical, demographic, and pathological factors.

Patients with TNBC who presented to the Cancer Genetics Department at Istanbul University Oncology Institute were included. Peripheral blood mononuclear cells were analyzed for BRCA1 and BRCA2 mutations using the Illumina MiSeq Next Generation Sequencing (NGS) platform. Patients were categorized as BRCA1 + or BRCA2+ (mutation carriers) or BRCA1- or BRCA2- (mutation non-carriers). Comparative analyses were conducted to identify differences between groups, and clustering analysis examined mutation patterns.

Among 485 TNBC patients, 119 (24.5%) carried pathogenic variants in BRCA1 and/or BRCA2 genes. Of these 119 carriers, 4 (0.8% of the total) harbored mutations in both genes. Specifically, 101 (20.8%) had BRCA1 + mutations, and 22 (4.5%) had BRCA2 + mutations. The carrier group had higher rates of bilateral breast cancer (BC) (14.3% vs. 4.9%), a family history of breast and ovarian cancer (BC and OC) (51.3% vs. 26%), and increased first-degree relative cancer cases. Bilateral BC was associated with a 2.748-fold increased risk of BRCA1 + mutations, while postmenopausal status reduced risk by 0.350-fold. Each additional first-degree BC case increased BRCA1 + mutation risk by 2.410-fold. Cluster analysis identified two distinct mutation patterns.

Turkish TNBC patients with BRCA1 + or BRCA2 + mutations exhibit unique clinical and familial characteristics, emphasizing the importance of genetic screening and familial risk evaluation in TNBC management. These findings underscore the clinical relevance of BRCA testing in TNBC patients for personalized screening and treatment strategies. Notably, this study provides the largest TNBC cohort (n = 485) reported from Türkiye, highlighting the significant role of BRCA1 in TNBC pathogenesis and offering a roadmap for individualized management.