Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

Valérie Paradis, Jessica Zucman-Rossi, Pierre Nahon, Marianne Ziol, Angela Sutton, Thierry Gustot, Jean-Pierre Bronowicki, Bruno Turlin, Carole Vitellius, Isabelle Archambeaud, Jacques Devière, Jean-Louis Guéant, Jean-Charles Nault, Viviane Gnemmi, Julien Calderaro, Eric Trépo, Jérôme Boursier, Patrick Hillon, Bruno Clément, Jean Frédéric Blanc, Cyrille Féray, Abderrahim Oussalah, Christophe Moreno, Nathalie Ganne-Carrié, Eric Letouzé, Quentin Bayard, Gabrielle Couchy, Sandrine Imbeaud, Jie Yang, Stefano Caruso

Journal: The Lancet. Oncology 2022;23(1):161-171

PMID: 34902334

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Abstract

BACKGROUND

Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma.

METHODS

We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts.

FINDINGS

The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10), PNPLA3 (rs738409; p=9·29 × 10), and HSD17B13 (rs72613567; p=2·49 × 10). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10), TM6SF2 (rs58542926; p=4·06 × 10), and PNPLA3 (rs738409; p=1·17 × 10). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis.

INTERPRETATION

WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.

FUNDING

Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

Address: Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France.; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Radiation Oncology, Peking University Third Hospital, Beijing, China.; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Service d'Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Paris, France.; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Regional and University Hospital Center of Nancy, Nancy, France; Reference Centre for Inborn Errors of Metabolism, Regional and University Hospital Center of Nancy, Nancy, France; INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, INSERM, Nancy, France.; Centre Hépato-Biliaire, Université Paris-Saclay, Paul Brousse Hospital, Assistance-Publique Hôpitaux de Paris, Paris, France.; Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France; Research in Translational Oncology, BaRITOn, Bordeaux, France.; INSERM U1241, INRAe U1341, Institute of Nutrition, Metabolisms and Cancer, CRB-Santé, The French Liver Biobank Network, Rennes University Hospital, University of Rennes, Rennes, France.; University of Bourgogne-Franche Comté, Dijon, France; INSERM U1231, Lipids, Nutrition, Cancer, University Hospital, Dijon, France; Department of Hepatogastroenterology, University Hospital, Dijon, France.; Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France; Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France.; Department of Pathology, Hôpital Beaujon, Assistance-Publique Hôpitaux de Paris, Clichy, France.; Service d'Anatomopathologie, Hôpital Henri Mondor, Assistance-Publique Hôpitaux de Paris Université Paris Est, Créteil, France; INSERM U955, Team 18, Institut Mondor de Recherche Biomédicale, Créteil, France.; University of Lille, CNRS, Inserm, CHU Lille, Pathology Department, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Regional and University Hospital Center of Nancy, Nancy, France; Reference Centre for Inborn Errors of Metabolism, Regional and University Hospital Center of Nancy, Nancy, France; INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, INSERM, Nancy, France; Department of Hepato-Gastroenterology, Hôpital de Brabois, CHRU de Nancy, University of Lorraine, Nancy, France.; Institut des Maladies de l'Appareil Digestif, Hôtel-Dieu, Nantes, France.; INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, INSERM, Nancy, France; Department of Hepato-Gastroenterology, Hôpital de Brabois, CHRU de Nancy, University of Lorraine, Nancy, France.; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Centre de Recherche sur l'inflammation, Inserm UMR S1149, Université de Paris, Paris, France.; Department of Biochemistry, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Paris, France; INSERM U1148 LVTS, UFR SMBH, Université Sorbonne Paris Nord, Paris, France.; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Centre de Ressources Biologiques Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Paris, France.; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: [email protected].

DOI: 10.1016/S1470-2045(21)00603-3