Assessing germline mutational profile and its clinicopathological associations in Triple Negative Breast Cancer

ABSTRACT Purpose Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25%) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are however predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in India Methods Using a multi-gene NGS (next-generation sequencing) panel of 26 ACMG recommended genes associated with inherited cancers. Results In our study cohort of 193 TNBC patients, we identified 57 pathogenic mutations of which BRCA1 (71.93%) and BRCA2 (14.03%) were most commonly mutated. Additionally, 8 pathogenic mutations were identified in non-BRCA genes associated with the HR pathway. 10 novel mutations were identified in 3 genes namely BRCA1 , BRCA2 and PALB2 . Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100K indicated that the novel mutations were unique. Furthermore, we identified 48 variants of uncertain significance (VUS) (24.9%). Conclusions Our study confirms the major proportion of mutations in BRCA1/2 genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Additionally, large scale studies are also warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.