Landscape of homologous recombination repair pathway germline NGS gene variants in a TNBC-rich cohort of Indian breast carcinoma patients.

Abstract

e22601 Background: According to the recent 2022-2024 published data from the GLOBOCAN, India alone contributed 15.5% of these cases with a staggering 26% of Breast carcinoma (BC) cases and 0.85 million people succumbed to the disease. Inherited or spontaneous mutations in HRR group of genes can disrupt DNA damage response signaling, impairing HRR and sensitizing cells to genotoxic insults. The current study brings to fore the spectrum of clinically significant and novel HRR pathway gene alterations in breast carcinoma patients with increased TNBC incidence. Methods: A total of 301, histologically diagnosed breast carcinoma patients were included for germline molecular assessment of HRR pathway genes via Ion Torrent NGS following manufacturer’s protocol from January,2019 to December,2023. Clinical summary and an informed consent were obtained individually from the patients. Results: Out of the total of 301 BC patients participated in the study, 119(39.53%) were diagnosed TNBC cases. NGS data revealed 76(25.2%) patients to harbour at least one clinically significant HRR pathway gene variant. Predominantly, BRCA2 was the most mutated gene (47.3%), followed by BRCA1 (43.4%) across patients. 41(34.4%) TNBC cases were detected with a pathogenic gene variant. In the mutation spectrum, exon-10 (27.9%) of BRCA1 and exon-11 (52.7%) of BRCA2 genes were the most mutated regions detected. Additionally, findings revealed 11 novel variants across HRR genes. Six novel variants in BRCA1 (exon-10, c.1039_1040insA, c.2841delA; exon-16, c .5009delG (02) and, exon-23, C.5519_5573del ) (02), four in BRCA2 (exon-10, c.1249_1250insT ; exon-11, c.4287_4288insT ; exon-14, c .7279_7280insC and exon-24, c.9241_9242insA ) and one in FANCD2 (exon-21, c.1900G>A) genes respectively. Also, BRCA1 founder mutation (185delAG) was also observed in two (2.6%) patients. CHEK2, PIK3CA, FANCD2 and TP53 were the other HRR pathway genes found positive in the cohort. Conclusions: Examining the complete BRCA gene status in patient cohort has enabled the identification of not only recurring pathogenic variants but also novel mutations. Among BC patients, an elevated frequency of TNBC patients (39.53%) is an alarming finding compared to the global incidence of 15-20%. The findings enable promising targeted therapeutic approaches by matching patients to treatments which is most likely to benefit them. With the views over the years and with the projected trends in the coming years, BC is set to remain in the driving seat, to drive the national and global cancer burden. Hence, population-based screening, population based molecular-genetic study updates and novel approaches in different strata of the disease are needed with the fast-moving cancer trend in the global society.