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

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

Gene Pub Date : 2026-03-15 Epub Date: 2025-12-30 DOI:10.1016/j.gene.2025.149989

Harshavardhani Canchi Sistla , Arun Seshachalam , Krishna Kumar Rathnam , Taruna Rajagopal , Srikanth Talluri , Subaranjana Saravanaguru Vasanthi , Nageswara Rao Dunna

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引用次数: 0

Abstract

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.

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DNA双链断裂修复基因变异（RAD51、XRCC2、XRCC3、XRCC4和LIG4）对卵巢癌易感性的综合病例对照和计算机分析

低外显率DNA修复基因（DRGs）对卵巢癌（OC）风险的贡献仍然知之甚少。同源重组修复（HRR）和非同源末端连接（NHEJ）途径基因的变异可能影响基因组稳定性并调节OC易感性。这项基于人群的病例对照研究（474名受试者，237名OC患者和237名对照）评估了RAD51、XRCC2、XRCC3 （HRR）和XRCC4、LIG4 （NHEJ）的多态性，以评估它们在OC易感性中的作用。使用PCR-RFLP进行基因分型，并进行logistic回归估计风险关联。多因素降维（MDR）分析检查了SNP-SNP相互作用，而在硅工具和静电表面作图预测了结构和功能效应。在RAD51 （rs1801320）中观察到显著的相关性，其中突变CC基因型个体的OC风险增加2.8倍（OR = 2.85; 95% CI = 1.15-7.06; p = 0.049），而CT基因型LIG4 （rs1805388）的风险增加1.85倍（OR = 1.85; 95% CI = 1.11-3.07; p = 0.0097）。相反，CT基因型携带者XRCC3 （rs861539）表现出较低的OC风险（OR = 0.49; 95% CI = 0.32-0.75; p = 0.003）。XRCC2和XRCC4无显著相关性。然而，XRCC2变异与肿瘤分级和绝经状态相关，XRCC3与肿瘤组织学相关。MDR分析显示，XRCC3与RAD51之间存在较强的相互作用，其次是涉及XRCC2的组合，提示HRR基因的协同作用。计算机预测表明，XRCC2 R188H具有不稳定性，XRCC3 T241M具有混合效应，而LIG4 T9I具有稳定性。总的来说，RAD51和LIG4多态性可能与南印度妇女的OC易感性有关。需要更大规模、多中心的研究来验证这些发现，并探索其作为卵巢癌预测生物标志物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gene 生物-遗传学

CiteScore

6.10

自引率

2.90%

发文量

718

审稿时长

42 days

期刊介绍： Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.