Spectrum of germline pathogenic and novel BRCA1 and BRCA2 gene mutations in a cohort of 1780 breast and ovarian carcinoma patients from east India.

Abstract

10614 Background: Advances in our understanding of the molecular basis of cancer have pushed us in a new era of personalized medicine in oncology. The adoption of personalized medicine in Breast cancer (BC) and Ovarian cancer (OC) care holds significant promise. Homologous recombination repair (HRR) process aids in the restoration of halted replication forks during DNA replication. Where, an effective HRR depends on the normal functioning of oncoproteins, BRCA1 and BRCA2 playing crucial roles. Methods: Germline Next Generation Sequencing based BRCA1 & BRCA2 gene panel on ion torrent technology was employed in 1780 diagnosed BC and OC patients for genetic-molecular evaluation. Bioinformatics pipelining and data analysis was performed as per Ion Reporter pre-designed stringent workflows for germline variant screening. Variants were called as per ACMG guidelines and framework. Results: A total of 993 (55.8%) BC, 673 (37.8%) OC and 114 (6.4%) patients with co-existing BC & OC participated in the study. Out of which, 232 (13%) patients were found to harbour a clinically significant BRCA1 or BRCA2 gene variant. Predominantly, BRCA1 was the most mutated gene (68%; n = 158), followed by BRCA2 (32%; n = 74) across cohort. 48.2% of BRCA variants were noted in BC while 41.7% in OC and 10.1% in co-existing BC & OC patients respectively. Majority of the pathogenic variants (55.4%) were detected in high-grade tumors with mean age of 45.2 years. Exon-10 (33.3%) of BRCA1 and exon-11 (47.2%) of BRCA2 genes were the most mutated regions detected. Additionally, findings revealed 21 (9.1%) novel (14 in BRCA1 and 07 in BRCA2 genes) variants across BRCA genes not reported previously in ClinVar (NCBI) or BIC (Breast Information Core) databases. BRCA1 gene, exon-02, c.68_69del (185delAG) was the most pre-dominant (10.3%) variant in the patient cohort. Conclusions: India has emerged as the global cancer capital with BC being the most incidental cancer in women. Investigating the BRCA1, BRCA2 gene status in the current patient cohort has enabled the identification of not only the recurring hotspot pathogenic variants but also novel variants, as per the NCCN guidelines with actionable targets. Among BC, elevated and alarming frequency of TNBC patients (37.5%) was noted. The study findings provide a wide spectrum of BRCA gene variants specific to East-Indian patients with novel gene mutations pertaining to Indian population. These findings support the development of targeted therapeutic strategies by enabling the alignment of individual patients with treatments most likely to confer clinical benefit. Such precision oncology approaches may improve therapeutic efficacy, minimize treatment related toxicity, and ultimately enhance quality of life among cancer patients. Keywords: Breast & Ovarian cancer; BRCA1; BRCA2; NGS; Precision therapeutics.