Genomic landscape and patterns of homologous recombination deficiency in Indian ovarian cancer: Clinical implications for precision therapy

Introduction: Ovarian carcinoma remains a leading cause of cancer-related mortality among women globally. However, the genomic characteristics of ovarian cancer in the Indian population are not well defined, limiting insights into ancestry-specific tumor biology and potential therapeutic targets. Methodology: Whole-exome sequencing data from 619 ovarian tumor samples from Indian patients were analyzed. After stringent quality control and filtering, 5,244 prioritized somatic variants were curated and classified according to AMP guidelines. Homologous recombination deficiency (HRD) scores were integrated with clinical metadata to examine associations between homologous recombination repair (HRR) gene alterations, HRD status, and clinicopathological features. Results: The median HRD score across the cohort was 47, with 47% of tumors classified as HRD-positive. Among clinically reported variants, 28.2% were classified as pathogenic or likely pathogenic (P/LP), 49.5% as variants of uncertain significance (VUS), and 22.1% remained unclassified. Recurrently altered driver genes included TP53 (64.9%), BRCA1 (38.6%), RAD50 (37.5%), CHEK1 (21.2%), and POLE (17.9%), indicating extensive disruption of DNA damage response (DDR) and HRR pathways. BRCA1/2 P/LP variants were detected in approximately 40.7% of tumors. HRD positivity was identified in both BRCA -mutated (48.0%) and non- BRCA -mutated tumors (46.3%), suggesting that HRR deficiency extends beyond BRCA1/2 alterations to include genes such as RAD50 , MRE11 , CHEK1 , CHEK2 , FANCA,andFANCD2 .Age-stratified analysis showed consistent frequencies of BRCA1/2 alterations and HRD positivity across all age groups (40-50% per stratum), indicating that HRR pathway disruption is widespread across clinical subgroups. Conclusions: This study represents one of the largest exome-based analyses of ovarian cancer in the Indian population. Nearly half of the tumors demonstrated HRD, and HRR pathway disruption was frequent even in the absence of BRCA1/2 mutations. These findings highlight the importance of comprehensive HRR gene testing and HRD evaluation to inform precision oncology approaches, including the use of PARP inhibitors and platinum-based therapies, for Indian ovarian cancer patients. Keywords: Ovarian carcinoma, Indian population, exome sequencing, homologous recombination deficiency, BRCA1 , TP53 , DNA repair, PARP inhibitors, precision oncology.