BRCA1 and BRCA2 gene mutation spectrum and high frequency of BRCA1 185delAG among breast and ovarian cancer patients from Southern India.

Abstract

Abstract In a developing country like India, genomic data sets for even the most clinically relevant genes like BRCA1 and BRCA2 are relatively scarce. There is also a need to identify and screen population specific BRCA hotspot mutations to pave the way for affordable genetic testing strategies in clinical practice. We have carried out an ambispective study to evaluate Next-generations Sequencing (NGS) based approach to identify pathogenic variants in BRCA1 and BRCA2 genes among 772 breast and ovarian cancer patients. The target enrichment was carried out using the in-house designed Multiplex-PCR for BRCA1 and BRCA2, followed by targeted NGS on Ion Torrent Personal Genome Machine. Additionally, allele-specific PCR (ASPCR) based genotyping of BRCA1 c.68_69delAG also known as 185delAG, was carried out in 149 patients. We identified 181 BRCA1 and BRCA2 variants, and based on ACMG 2015 guidelines, these variants were classified as 111 pathogenic or likely pathogenic and 70 VUS (Variant with uncertain significance). The 185delAG was identified as a recurrent mutation in the Southern Indian population accounting for 25.21% of the pathogenic variants. In addition, a family history of cancers of the breast, ovary, pancreas, or prostate (BOPP) was found to be associated with a higher risk of identifying a deleterious BRCA1/2 variant [OR=2.15 (95%CI 1.46-3.2) p≤0.0001]. These results suggest that Multiplex PCR coupled NGS is a sensitive and specific strategy for BRCA testing. However, ASPCR-based genotyping of 185delAG followed by targeted NGS would be cost-effective in South Indian patients.