Genetic variants of the dUTPase-encoding gene DUT increase HR-HPV infection rate and cervical squamous cell carcinoma risk

Abstract

Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is involved in the repair and prevention of uracil misincorporations into DNA. Maintenance of DNA integrity is critical for cancer prevention. Many studies have identified susceptibility loci and genetic variants in cervical cancer. The aim of this study was to explore the distribution frequency of six single nucleotide polymorphisms (SNPs) in the dUTPase-encoding gene DUT in a case-control study to identify the relationship between DUT genetic variants and cervical cancer susceptibility. Six DUT intronic SNPs (rs28381106, rs3784619, rs10851465, rs28381126, rs3784621 and rs11637235) were genotyped by mismatch amplification-PCR in 400 cervical squamous cell carcinomas (CSCCs), 400 precursor cervical intraepithelial neoplasia (CIN) III lesions and 1,200 normal controls. No correlations were found between four DUT SNPs (rs3784621, rs10851465, rs28381106 and rs28381126) and CIN III and CSCC risk. However, the homozygous GG allele of rs3784619 and TT allele of rs11637235 correlated significantly with increased risk of CIN III and CSCC (OR = 2.29, 2.05; OR = 3.15, 3.15, respectively). Individuals with the G allele or G carrier allele (AG + GG) at rs3784619 and with the T allele or T carrier allele (CT + TT) at rs11637235 were at higher risk for CIN III and CSCC (OR = 1.26, 1.30; OR = 1.41, 1.65, respectively). Similarly, in the human papillomavirus (HPV)-positive groups, we found that the homozygous GG alleles of rs3784619 and TT alleles of rs11637235 markedly increased the risk of CIN III and CSCC (OR = 2.44, 2.71; OR = 3.32, 4.04, respectively). When performing a stratified analysis of sexual and reproductive histories, we found that the GG genotype of rs3784619 had a particularly high level of enrichment in the group of patients with > one sexual partner in CIN III (P = 0.043) and CSCC (P = 0.007). Meanwhile, the TT genotype of rs11637235 was enriched for in the high risk HPV (HR-HPV)-positive cases of CIN III (P = 0.033) and CSCC (P = 0.022). Analysis of the haplotype between rs3784619 (A/G) and rs11637235 (C/T) revealed that the genotypes with AA-TT (OR = 2.59), AG-TT (OR = 2.29), GG-CC (OR = 2.72), GG-CT (OR = 3.01 (1.83–4.96)) were significantly associated with increased risk of CIN III. More notably, this risk was much greater for CSCC (AA-TT (OR = 3.62), AG-TT (OR = 5.08), GG-CC (OR = 5.28), and GG-CT (OR = 4.23). Additionally, most GG genotypes of rs3784619 were linkage GG-CT, while most TT genotypes of rs11637235 were linkage AA-TT. In conclusion, these findings suggested that the homozygous GG allele of rs3784619 and the TT allele of rs11637235 in the DUT gene significantly increased the risk of CIN III and CSCC. Most GG genotypes of rs3784619 and TT genotypes of rs11637235 were linkage GG-CT and AA-TT, respectively. The TT genotype of rs11637235 was enriched in the HR-HPV-positive cases. These two SNPs of the DUT gene can be early predictive biomarkers of CIN III and CSCC, and may be involved in HR HPV infection.