Abstract
Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes (SNAIL1, ZEB1, ZEB2, TWIST1) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The SNAIL1rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC vs. TT: OR=1.559; 95% confidence interval [CI], 1.073-2.264; P=0.020) and CHB+LC (CT+CC vs. TT: OR=1.509; 95% CI, 1.145-1.988; P=0.003). Carriers of the TWIST1rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC vs. GG: OR=1.407; 95% CI, 1.065-1.858; P=0.016). The ZEB2rs3806475T>C was associated with significantly increased risk of both HCC (P recessive =0.001) and CHB+LC (P recessive<0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients (P=0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients (P=0.0123). In MDR analysis, the combination of TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC.
Highlights
Hepatocellular carcinoma (HCC), a common malignant tumour of the digestive system, is the second leading cause of cancerrelated death in China
We hypothesized that epithelial-mesenchymal transition (EMT) genes play an important role in HCC and chronic hepatitis B virus (HBV) infection, and that environment-gene and genegene interactions are important
We found significant genetic associations for single EMT genes with HCC and chronic HBV infection, as well as environment-gene and gene-gene interactions
Summary
Hepatocellular carcinoma (HCC), a common malignant tumour of the digestive system, is the second leading cause of cancerrelated death in China. HCC is characterized by high malignant potential, concealed pathogenesis, rapid progress, poor prognosis and a high mortality rate. It is typically diagnosed during the middle and late disease stages, when surgery is no longer a viable option [1]. Three well-established transcriptional regulatory groups have been identified as important factors in regulating the Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; CHB, chronic hepatitis B; LC, liver cirrhosis; EMT, epithelial-mesenchymal transition; SNP, single-nucleotide polymorphism; LD, linkage disequilibrium; MDR, multifactor dimensionality reduction; MAF, minor allele frequency; mean ± SD, mean ± standard deviation; M(QR), median(quartile interval); OR, odds ratio; CI, confidence interval; EDTA, ethylenediamine-tetra-acetic acid; 3'-UTR, 3'-untranslatedregion
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