Identification of modifier genes predisposing to breast cancer (BC) phenotype remains a significant challenge and varies with ethnicity. The genetic variability observed in DNA repair genes may modulate the cell’s ability to repair the damaged DNA and hence, evaluation of genetic variants in crucial DNA damage repair genes is of clinical importance. We performed the present study to evaluate the role of ERCC2-Lys751Gln, hOGG1-Ser326Cys, and XRCC1-Arg399Gln gene polymorphisms on the risk of BC development and its molecular profile in Indian women. Three non-synonymous variants (rs13181, rs1052133, and rs25487) were genotyped in 464 BC patients and 450 healthy controls. Logistic regression was employed to evaluate the association of genotypes with BC risk. Also, in silico analysis was carried out to map the Arg399Gln variant on the BRCT1 domain of XRCC1 protein. XRCC1 Gln/Gln genotype frequency was significantly elevated in BC patients [odd ratio (OR) = 1.73; 95% confidence interval (CI) = 1.13–2.65]. No significant association was observed between hOGG1-Ser326Cys and ERCC2-Lys751Gln variants and BC risk. Subgroup analysis revealed that ERCC2-Lys751Gln and XRCC1-Arg399Gln variants contributed towards tumor progression. A positive interaction between the investigated SNPs and BC was revealed by MDR analysis. Arg399Gln variant resulted in a change in the surface charge of XRCC1 protein. The rs25487 variant of XRCC1 might be associated with an elevated risk of BC. Furthermore, we demonstrated that high order gene–gene interaction plays a significant role in BC etiology. Hence, understanding the impact of low penetrant gene polymorphisms might enable a better understanding of the genetic background of breast cancer.

易患乳腺癌（BC）表型的修饰基因的鉴定仍然是一项重大挑战，并且因种族而异。在DNA修复基因中观察到的遗传变异性可能会调节细胞修复受损DNA的能力，因此，评估关键DNA损伤修复基因中的遗传变异具有临床重要性。我们进行本研究，以评估的作用ERCC2 - Lys751Gln，hOGG1基因- Ser326Cys，和XRCC1 - Arg399Gln基因多态性与印度女性BC发展风险及其分子谱的关系。在464例BC患者和450例健康对照中对3个非同义变体（rs13181，rs1052133和rs25487）进行了基因分型。采用逻辑回归分析评估基因型与BC风险之间的关系。此外，进行了计算机分析，以将Arg399Gln变体定位在XRCC1蛋白的BRCT1域上。XRCC1 Gln / Gln基因型频率在BC患者中显着升高[比值比（OR）= 1.73；95％置信区间（CI）= 1.13–2.65]。未见显著相关性之间hOGG1基因- Ser326Cys和ERCC2 - Lys751Gln变异和BC风险。亚组分析显示，ERCC2 - Lys751Gln和XRCC1 - Arg399Gln变体有助于肿瘤进展。通过MDR分析揭示了所研究的SNP与BC之间的正相互作用。Arg399Gln变异导致XRCC1蛋白表面电荷的变化。XRCC1的rs25487变体可能与BC风险升高有关。此外，我们证明了高阶基因-基因相互作用在BC病因中起着重要作用。因此，了解低渗透基因多态性的影响可能使人们更好地了解乳腺癌的遗传背景。