A putative hepatitis B virus sequence motif associated with hepatocellular carcinoma in South African adults

Abstract

ABSTRACTAimChronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) particularly in African populations, in whom malignancy frequently presents at an advanced stage 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.ResultsCompared 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 which 96% were subtype A1. PreS2 deletions (Δ38–55) were enriched in HBV sequences from HCC patients (n = 7). The sequence motif most strongly associated with HCC comprised either deletion or polymorphism at site T53 in PreS2 – collectively coined ‘non-T53’ – together with a basal core promoter (BCP) mutation G1764A (AUROC 0.79).ConclusionsIn this setting, HBV sequence polymorphisms and deletions are associated with HCC, and ‘non-T53 + G1764A’ represents a putative signature motif for HCC. Additional investigations are needed to disaggregate the impact of age, sex and HIV status, to ascertain the extent to which viral polymorphisms contribute to oncogenesis, and to determine whether HBV sequence is a useful biomarker for risk stratification.