Functional FOXA2 3’UTR variant rs1055080 is associated with HBV-related hepatocellular carcinoma risk and postoperative prognosis

Hepatocarcinogenesis is predominantly driven by chronic hepatitis B virus (HBV) infection. Although the transcription factor FOXA2 is known to regulate hepatic development and metabolism, the impact of its genetic predisposition on HBV-related hepatocellular carcinoma (HBV-HCC) remains unclear. We performed a case-control analysis in 4,921 Chinese participants. Two candidate functional single nucleotide polymorphisms (SNPs) (rs1209523 at the promoter region and rs1055080 at the 3’UTR region) in FOXA2 were genotyped. The functions of FOXA2 SNPs were evaluated by dual-luciferase reporter assays. The prognostic values of FOXA2 SNPs were evaluated in a postoperative cohort study of 367 patients with HBV-HCC. The frequency of the rs1055080-T allele was significantly associated with reduced risk of HBV-HCC. This association was evident when HBV-HCC patients were compared with asymptomatic HBV carriers and patients with chronic hepatitis B. In reporter assays, rs1055080-T showed higher FOXA2 3’UTR reporter activity than rs1055080-C. Reporter constructs carrying the rs1055080-C allele showed stronger repression by miR-328-3p or miR-3615 than those carrying rs1055080-T. rs1055080-T was significantly associated with lower frequencies of HCC-risk HBV mutations. Reporter activity of the rs1055080-C construct decreased in the presence of A1762T/G1764A. rs1055080-CT + TT was associated with better overall survival in HBV-HCC. These findings suggest that the FOXA2 3’UTR variant is a candidate germline marker for risk stratification and prognostic assessment in HBV-infected subjects.