Uncovering Hereditary Risk: Germline Homologous Recombination Repair Variant Spectrum in a Large North Indian Cancer Cohort (INSIGHT-HRR).

Abstract

Homologous recombination repair (HRR) pathway defects are critical drivers of hereditary cancers, yet population-specific prevalence data from India remain limited. Current testing practices disproportionately focus on <i>BRCA1/2</i>, potentially underidentifying patients with other HRR gene variants who could benefit from targeted therapies. A retrospective observational cohort study was conducted, analyzing 950 consecutive patients who underwent next generation sequencing-based germline testing at the Cancer Genetics Clinic, Mahamana Pandit Madanmohan Malaviya Cancer Centre, Varanasi. The core HRR panel included <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, <i>RAD51C</i>, <i>RAD51D</i>, <i>ATM</i>, <i>CHEK2</i>, <i>BRIP1</i>, <i>BARD1</i>, <i>RAD50</i>, <i>NBN</i>, <i>MRE11</i>, and <i>FANCC</i>. Of 950 patients analyzed, 364 (38.3%) harbored variants in HRR genes, with 266 (28%) carrying pathogenic/likely pathogenic (P/LP) variants<i>. BRCA1</i> was the most frequently altered gene (182/266, 68.4% of P/LP variants), followed by <i>BRCA2</i> (37/266, 13.9%). Combined BRCA1/2 genetic variants accounted for 219/266 (82.3 17%) of all P/LP variants. Non-<i>BRCA</i> HRR genes contributed 47/266 (17.6%) P/LP variants, with <i>PALB2</i> being the most common (14/266, 5.2%). The study identified 98 variants of uncertain significance across the HRR genes. This large Indian cohort demonstrates a high prevalence of HRR gene alterations, with significant contribution from non-<i>BRCA</i> genes. These findings support the implementation of comprehensive HRR gene panels in Indian populations and highlight the therapeutic implications for poly (ADP-ribose) polymerase inhibitor and platinum-based treatment strategies.