Full-length deep sequencing of South African HBV in adults with HCC. Full-length deep sequencing of South African Hepatitis B Virus (HBV) reveals increased diversity and frequent deletions in adults with hepatocellular carcinoma (HCC)

Background: The global burden of hepatocellular carcinoma (HCC) is increasing, with climbing incidence and mortality rates. Chronic hepatitis B virus (HBV) infection is a leading risk factor, accounting for a substantial majority of all cases in some settings, including sub-Saharan Africa where disease presents late and outcomes are poor. Deriving HBV full genome sequences from patients with HCC may support new insights into mechanisms of oncogenesis, offer improvements in early diagnosis, provide prognostic information, and underpin the design of new interventions. Methods: We here present the results of HBV sequencing using Illumina, comparing data from adults with HCC and without HCC from the Western Cape, South Africa. Results: Compared to non-HCC cases, a significantly larger percentage of HCC patients were more likely to be male. HCC patients reported significantly higher median HBV DNA viral loads. Genotype A infected HCC patients were not significantly younger than those with genotype D/E. We generated full length deep HBV sequence data from 19 HCC and 12 non-HCC patients. Genetic diversity was significantly higher in HBV from HCC compared to non-HCC, and polymorphisms were more frequent. Multiple deletions were apparent in Illumina data, being observed in Illumina consensus data, especially concentrated in the BCP, pre-core/core (overlapping with X), and pre-S1/S2 region(s). Conclusions: In this setting, HBV sequence polymorphisms and deletions are associated with HCC and genotype A is associated with HCC at a younger age. More work is needed to ascertain the extent to which viral polymorphisms may contribute to oncogenesis, and to determine whether they are useful biomarkers to help with risk stratification.