Comprehensive investigating of MMR gene in hepatocellular carcinoma with chronic hepatitis B virus infection in Han Chinese population

Ning Ma; Ao Jin; Yitong Sun; Yiyao Jin; Yucheng Sun; Qian Xiao; XuanYi Sha; Fengxue Yu; Lei Yang; Wenxuan Liu; Xia Gao; Xiaolin Zhang; Lu Li

doi:10.3389/fonc.2023.1124459

Comprehensive investigating of MMR gene in hepatocellular carcinoma with chronic hepatitis B virus infection in Han Chinese population

Front Oncol. 2023 Mar 24:13:1124459. doi: 10.3389/fonc.2023.1124459. eCollection 2023.

Authors

Ning Ma¹, Ao Jin², Yitong Sun², Yiyao Jin², Yucheng Sun², Qian Xiao², XuanYi Sha³, Fengxue Yu⁴, Lei Yang², Wenxuan Liu², Xia Gao², Xiaolin Zhang², Lu Li¹

Affiliations

¹ Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China.
² Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China.
³ Hebei Key Laboratory of Environment and Human Health, School of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
⁴ The Hebei Key Laboratory of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Abstract

Hepatocellular carcinoma associated with chronic hepatitis B virus infection seriously affects human health. Present studies suggest that genetic susceptibility plays an important role in the mechanism of cancer development. Therefore, this study focused on single nucleotide polymorphisms (SNPs) of MMR genes associated with HBV-HCC. Five groups of participants were included in this study, which were healthy control group (HC), spontaneous clearance (SC), chronic hepatitis B group (CHB), HBV-related liver cirrhosis group (LC) and HBV-related hepatocellular carcinoma group (HBV-HCC). A total of 3128 participants met the inclusion and exclusion criteria for this study. 20 polymorphic loci on MSH2, MSH3 and MSH6 were selected for genotyping. There were four case-control studies, which were HC vs. HCC, SC vs. HCC, CHB vs. HCC and LC vs. HCC. We used Hardy-Weinberg equilibrium test, unconditional logistic regression, haplotype analysis, and gene-gene interaction for genetic analysis. Ultimately, after excluding confounding factors such as age, gender, smoking and drinking, 12 polymorphisms were found to be associated with genetic susceptibility to HCC. Haplotype analysis showed the risk haplotype GTTT (rs1805355_G, rs3776968_T, rs1428030_C, rs181747_C) was more frequent in the HCC group compared with the HC group. The GMDR analysis showed that the best interaction model was the three-factor model of MSH2-rs1981928, MSH3-rs26779 and MSH6-rs2348244 in SC vs. HCC group (P=0.001). In addition, we found multiplicative or additive interactions between genes in our selected SNPs. These findings provide new ideas to further explore the etiology and pathogenesis of HCC. We have attempted to explain the molecular mechanisms by which certain SNPs (MSH2-rs4952887, MSH3-rs26779, MSH3-rs181747 and MSH3-rs32950) affect genetic susceptibility to HCC from the perspectives of eQTL, TFBS, cell cycle and so on. We also explained the results of haplotypes and gene-gene interactions. These findings provide new ideas to further explore the etiology and pathogenesis of HCC.

Keywords: HBV; HCC; MMR; SNP; haplotype; interaction.

Grants and funding

The study was financially supported by the Natural Science Foundation of Hebei Province (H2022206209,H2021206401). Hebei Medical University 2022 National Innovative Experimental Program for Undergraduates (USIP2022006). Hebei Medical University 2022 Provincial Innovative Experimental Program for Undergraduates (USIP2022104). National Natural Science Foundation of China (No. 82101760).