Integrated case-control and in silico analysis of DNA double-strand break repair gene variants (RAD51, XRCC2, XRCC3, XRCC4, and LIG4) for ovarian cancer susceptibility.

The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case-control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in RAD51, XRCC2, XRCC3 (HRR), and XRCC4, LIG4 (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP-SNP interactions, while in silico tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for RAD51 (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15-7.06; p = 0.049), and the CT genotype of LIG4 (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11-3.07; p = 0.0097). Conversely, CT genotype carriers of XRCC3 (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32-0.75; p = 0.003). XRCC2 and XRCC4 showed no significant associations. However, XRCC2 variants correlated with tumor grade and menopausal status, and XRCC3 with tumor histology. MDR analysis revealed strong interactions between XRCC3 and RAD51, followed by combinations involving XRCC2, suggesting synergistic HRR gene effects. In silico predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, RAD51 and LIG4 polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.