Liver intestine-cadherin (CDH17) haplotype is associated with alternative mRNA splicing and increased risk of hepatocellular carcinoma

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common liver malignancy with high mortality worldwide. Our previous study demonstrated that aberrant mRNA splicing of liver intestine (LI)-cadherin gene CDH17 was associated with tumor dissemination and shorter survival of HCC patients. In this study, we aim to investigate the potential link between CDH 17 haplotypes and alternative splicing in HCC. METHODS: One hundred and sixty-four HCC and 99 cirrhosis patients, and 258 healthy controls were investigated for genetic polymorphisms of CDH17 using PCR and sequencing. Odds ratio and χ2 analysis were used to analyze genotypes and haplotypes. RESULTS: CDH17 651T (C > T) and IVS6 + 35G (A > G) alleles were overrepresented in HCC patients, especially genotypes 651 TT (OR, 2.59; 95% CI, 1.35–4.97) and IVS6 + 35 GG (OR, 1.91; 95% CI, 1.03–3.53) were highly associated with HCC disease. The T-G haplotype was more prevalent in HCC patients compared with healthy controls (OR, 1.57; 95% CI, 1.167–2.109; P = 0.004). The mini-gene assay revealed that the T and G allelic combination could result in exon 7 or both exons 6 and 7 skipping of CDH17 mRNA, indicating that the T-G haplotype might alter the mRNA splicing of LI-cadherin. There was no significant difference in genotype and allele frequencies between the cirrhosis and control groups. However, the allelic frequencies of 651T and IVS6 + 35G significantly increased in a trend of control, cirrhosis toward HCC. CONCLUSION: The functional T-G haplotype of CDH17 (651 C > T and IVS6 + 35 A > G) is a genetic susceptibility factor for the development of HCC in a Chinese population.