Hepatitis B virus preS2Δ38–55 variants: A newly identified risk factor for hepatocellular carcinoma

Abstract

Background & Aims: Although HBV is a major cause of death in Africa, its genetic variability has been poorly documented. This study aimed to address whether HBV genotype and surface gene variants are associated with HBV-related liver disease in The Gambia. Methods: We conducted a case-control study nested in the Prevention of Liver Fibrosis and Cancer in Africa programme. Consecutive treatment-naive patients with chronic HBV infection and detectable viral load were recruited: 211 controls with no significant liver disease and 91 cases (56 cirrhosis and 35 HCC cases). HBV genotypes and surface gene variants were determined by Sanger sequencing or next-generation sequencing (NGS) in serum DNA. Aflatoxin B1 (AFB1)-specific codon 249 TP53 mutation was determined by NGS in circulating cell-free plasma DNA. Results: In phylogenetic analysis, 85% of individuals carried HBV genotype E, 14% genotype A, and 1% A/E recombinant viruses. Surface gene variants were more frequently observed in cases (43% and 57% in cirrhosis and HCC cases, respectively) than controls (25%; p <0.001), with preS2 deletions between nucleotides 38-55 (preS2D38-55) being the main genetic variant detected. In multivariable analysis, HBeAg seropositivity, low HBsAg levels, and HDV seropositivity were significantly associated with cirrhosis and HCC, whilst older age, higher viral load, genotype A, preS2D38-55, and AFB1 exposure were only associated with HCC. There was a multiplicative joint effect of preS2D38-55 variants with HBeAg seropositivity (odds ratio [OR] 43.1 [10.4-177.7]), high viral load >2,000 IU/ml (OR 22.7 [8.0-64.9]), HBsAg levels <10,000 IU/ml (OR 19.0 [5.5-65.3]), and AFB1 exposure (OR 29.3 [3.7-230.4]) on HCC risk. Conclusions: This study identified a hotspot for HBV preS2 deletions as a strong independent factor for HCC in The Gambia, with HBV genotypes and AFB1 exposure contributing to the high liver cancer risk.

Hepatitis B Virus Genotype Study in West Africa Reveals an Expanding Clade of Subgenotype A4

“…We investigated samples from patients enrolled in the Prolifica (Prevention of liver fibrosis and cancer in Africa) program from The Gambia [ 24 ] and Senegal. The Gambia Government/Medical Research Council (MRC) Joint Ethics Committee (SCC 1266 West African Treatment Cohort for Hepatitis B) validated this study.…”

Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence

“…Mutations in HBsAg (particularly in the PreS region) have been linked to endoplasmic reticulum stress (both in vitro [ 106 , 107 ] and in animal models [ 108 , 109 ]) and there is evidence that these cells clonally expand in patient livers, suggesting it confers a survival advantage to the cells [ 106 , 110 , 111 ]. These HBsAg mutants and the “ground-glass” histological change they induce in liver tissues are indeed more frequent in patients with HCC [ 112 , 113 , 114 ], though exact mechanisms behind this association remain to be fully characterised.…”

Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma

“…The presence of pre-S gene deletions in the blood was evaluated as an independent risk factor for liver cirrhosis and HCC development [ 25 , 26 ]. Moreover, Cohen et al showed that the presence of pre-S2 gene deletions between nts 38 and 55 (a 12 nt, 15-nt, or 18 nt deletion) in the blood independently predicted HCC development [ 27 ]. Collectively, these results suggest a clinical correlation between pre-S gene deletions and HBV-related liver cirrhosis and HCC development.…”