Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, P. R. China.
Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, P. R. China.
Sci Rep. 2019 Jan 24;9(1):513. doi: 10.1038/s41598-018-36757-7.
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.
脱氧尿苷三磷酸核苷水解酶（dUTPase）参与修复和预防尿嘧啶错误掺入 DNA。维护 DNA 完整性对于预防癌症至关重要。许多研究已经确定了宫颈癌的易感基因座和遗传变异。本研究旨在通过病例对照研究探讨 dUTPase 编码基因 DUT 中六个单核苷酸多态性（SNP）的分布频率，以确定 DUT 遗传变异与宫颈癌易感性之间的关系。通过错配扩增-PCR 对 400 例宫颈鳞状细胞癌（CSCC）、400 例宫颈上皮内瘤变（CIN）III 病变和 1200 例正常对照进行了六个 DUT 内含子 SNP（rs28381106、rs3784619、rs10851465、rs28381126、rs3784621 和 rs11637235）的基因分型。四个 DUT SNP（rs3784621、rs10851465、rs28381106 和 rs28381126）与 CIN III 和 CSCC 风险之间没有相关性。然而，rs3784619 的 GG 纯合子等位基因和 rs11637235 的 TT 等位基因与 CIN III 和 CSCC 的风险显著增加相关（OR=2.29,2.05；OR=3.15,3.15，分别）。rs3784619 处的 G 等位基因或 G 携带等位基因（AG+GG）和 rs11637235 处的 T 等位基因或 T 携带等位基因（CT+TT）的个体患 CIN III 和 CSCC 的风险更高（OR=1.26,1.30；OR=1.41,1.65，分别）。同样，在 HPV 阳性组中，我们发现 rs3784619 的 GG 纯合子等位基因和 rs11637235 的 TT 等位基因显著增加了 CIN III 和 CSCC 的风险（OR=2.44,2.71；OR=3.32,4.04，分别）。当对性行为和生殖史进行分层分析时，我们发现 rs3784619 的 GG 基因型在 CIN III 中具有≥1 个性伴侣的患者中高度富集（P=0.043）和 CSCC（P=0.007）。同时，rs11637235 的 TT 基因型在高危型 HPV（HR-HPV）阳性的 CIN III（P=0.033）和 CSCC（P=0.022）中富集。rs3784619（A/G）和 rs11637235（C/T）之间的单倍型分析表明，AA-TT（OR=2.59）、AG-TT（OR=2.29）、GG-CC（OR=2.72）、GG-CT（OR=3.01（1.83-4.96））基因型与 CIN III 风险显著相关。更值得注意的是，这种风险对于 CSCC 来说更大（AA-TT（OR=3.62）、AG-TT（OR=5.08）、GG-CC（OR=5.28）和 GG-CT（OR=4.23）。此外，rs3784619 的大多数 GG 基因型为 GG-CT，而 rs11637235 的大多数 TT 基因型为 AA-TT。总之，这些发现表明，DUT 基因中 rs3784619 的 GG 纯合子等位基因和 rs11637235 的 TT 等位基因显著增加了 CIN III 和 CSCC 的风险。rs3784619 的大多数 GG 基因型和 rs11637235 的 TT 基因型分别为 GG-CT 和 AA-TT。rs11637235 的 TT 基因型在 HR-HPV 阳性病例中富集。这两个 DUT 基因的 SNP 可以作为 CIN III 和 CSCC 的早期预测生物标志物，并且可能参与 HR-HPV 感染。
