Elucidation of Increased Cervical Cancer Risk Due to Polymorphisms in XRCC1 (R399Q and R194W), ERCC5 (D1104H), and NQO1 (P187S).

Abstract

Genetic variations like single nucleotide polymorphisms (SNPs) are associated with cervical carcinogenesis. In this study, SNPs have been identified that contribute toward changes in the function and stability of the proteins and show association with cervical cancer. Initially, literature mining identified 114 protein-coding polymorphisms with population-based evidence in cervical cancer. Subsequently, the functional assessment was performed using sequence-dependent tools, and thereafter, protein stability was analyzed using sequence and structural data. Twenty-three non-synonymous SNPs (nsSNPs) found to be damaging and destabilizing were then analyzed to check their risk association at the population level. The meta-analysis indicated that polymorphisms in DNA damage repair genes XRCC1 (rs25487 and rs1799782), ERCC5 (rs17655), and oxidative stress-related gene NQO1 (rs1800566) are significantly associated with increased cervical cancer risk. The XRCC1 rs25487 and rs1799782 polymorphisms showed the highest risk of cervical cancer in the homozygous model having odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17-2.92, p = 0.01, and recessive model with OR = 1.81, 95% CI = 1.01-3.24, and p = 0.04 respectively. Similarly, rs17655 polymorphism of ERCC5 and rs1800566 polymorphism of NQO1 showed the highest pooled OR in the homozygous (OR = 1.70, 95% CI = 1.32-2.19, p = 0.00004) and heterozygous model (OR = 1.3, 95% CI = 1.06-1.58, p = 0.01) respectively. Thus, in this study, a comprehensive collection of nsSNPs was collated and assessed, leading to the identification of polymorphisms in DNA damage repair and oxidative stress-related genes, that destabilize the protein and shows increased risk associated with cervical cancer.