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Abstract Details
Hepatitis B virus preS2?38-55 variants: A newly identified risk factor for hepatocellular carcinoma
Damien Cohen1, Sumantra Ghosh1, Yusuke Shimakawa2, Njie Ramou3, Pierre Simon Garcia45, Anaëlle Dubois1, Clément Guillot1, Nora Kakwata-Nkor Deluce1, Valentin Tilloy6, Geoffroy Durand3, Catherine Voegele3, Gibril Ndow7, Umberto d'Alessandro7, Céline Brochier-Armanet4, Sophie Alain6, Florence Le Calvez-Kelm3, Janet Hall1, Fabien Zoulim18, Maimuna Mendy3, Mark Thursz9, Maud Lemoine9, Isabelle Chemin1
Author information
1INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
2Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France.
3International Agency for Research on Cancer, Lyon, France.
4Univ Lyon, Université Lyon 1, CNRS, UMR5558, Laboratoire de Biométrie et Biologie Évolutive, Villeurbanne, France.
5Molecular Microbiology and Structural Biochemistry, Institut de Biologie et de Chimie des Protéines 7 passage du Vercors, Lyon Cedex, France.
6Microbiology Department, CHU Limoges, Genomic Platform GenoLim, UMR Inserm 1092/FR CNRS 145 GEIST, Faculté de Médecine-Université de Limoges, CHU Dupuytren, CBRS, Limoges, France.
7Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.
8Department of Hepatology, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France.
9Department of Metabolism, Digestion and Reproduction, Liver Unit, Imperial College London, London, UK.
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 (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.