Hepatitis B virus preS2Δ38–55 variants: A newly identified risk factor for hepatocellular carcinoma
Damien Cohen, Sumantra Ghosh, Yusuke Shimakawa, Ramou Njie, Pierre Garcia, A. Dubois, Clément Guillot, Nora Kakwata-Nkor Deluce, Valentin Tilloy, Geoffroy Durand, Catherine Voegele, Gibril Ndow, Umberto D’Alessandro, Céline Brochier‐Armanet, Sophie Alain, Florence Le Calvez‐Kelm, Janet Hall, Fabien Zoulim, Maimuna Mendy, Mark Thursz, Maud Lemoine, Isabelle Chemin
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: mutation was determined by NGS in circulating cell-free plasma DNA. RESULTS: <0.001), with preS2 deletions between nucleotides 38-55 (preS2Δ38-55) 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, preS2Δ38-55, and AFB1 exposure were only associated with HCC. There was a multiplicative joint effect of preS2Δ38-55 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. LAY SUMMARY: Although HBV-related liver disease is highly prevalent in sub-Saharan Africa, the associated virological characteristics are poorly studied. Using clinical data from African patients chronically infected with HBV, an assessment of the virological variability (genotypes and mutations) and exposure to AFB1, a toxin often contaminating food, was carried out. Our results show that HBV genotypes, the presence of a highly prevalent mutant form of HBV, and AFB1 exposure contribute to the high liver cancer risk in this population.