Genome-wide association study of HBV-related hepatocellular carcinoma identifies a functional variant at the FAM114A1 locus

Liver cancer ranks sixth in cancer incidence and third in cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the primary histological subtype, and hepatitis B virus (HBV) carriers have a higher risk of HCC. Although several susceptibility loci for HCC have been identified in East Asian populations through genome-wide association studies (GWAS), the underlying biological mechanisms of this malignancy remain incompletely understood. Here, we conduct a two-stage GWAS including 2413 cases and 2794 HBV-positive controls from a high-incidence region in Southern China. The function of the susceptibility locus is investigated by bioinformatic and experimental approaches, supported by a xenograft model. We identify a 4p14 locus significantly associated with the risk of HCC (rs55718051, OR [95% CI] = 0.73 [0.67-0.80], Pmeta = 9.14 × 10⁻¹¹), and 18q23 locus with borderline significance (rs12964643: OR [95% CI] = 0.75 [0.67-0.83], Pmeta = 1.11 × 10⁻⁷). Functional experiments indicate the role of rs55718051 in FAM114A1 expression regulation, possibly through interaction of FOXA1. Knockdown of FAM114A1 significantly enhances the oncogenic phenotypes in liver cancer cells, suggesting its potential tumor suppressor role. Our findings expand the understanding of HCC susceptibility and suggest FAM114A1 as a potential suppressor in HBV-related HCC carcinogenesis.