HBV sequence motif associated with HCC in Sth African adults

Aim: Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) particularly in African populations, in whom disease frequently presents at an advanced stage and with poor outcomes. We derived HBV whole genome sequences (WGS) from individuals with HCC and compared them to sequences from individuals without HCC. Methods: We identified adults with HBV infection, with and without complicating HCC, in Cape Town, South Africa and utilized pan-genotypic probe-based enrichment followed by Illumina sequencing to derive HBV WGS. Results: Compared to the non-HCC group, HCC patients were more likely to be male (p < 0.0001), older (p = 0.01), HIV-negative (p = 0.006), and to have higher HBV viral loads (p < 0.0001). Among 19 HCC and 12 non-HCC patients, genotype A dominated (74% of sequences), of which 96% were subtype A1. PreS2 deletions (?38–55) were enriched in sequences from HCC patients (n = 7). The sequence motif most strongly associated with HCC comprised either deletion or polymorphism at site T53 – collectively coined 'non-T53' – in PreS2 together with a basal core promoter (BCP) mutation G1764A (AUROC 0.79). Conclusions: In this setting, HBV sequence polymorphisms and deletions are associated with HCC, and the non-T53 + G1764A represents a signature motif for HCC. Additional investigations are needed to ascertain the extent to which viral polymorphisms contribute to oncogenesis and to determine whether these may represent useful biomarkers for risk stratification.