Eric Trépo1, Stefano Caruso2, Jie Yang3, Sandrine Imbeaud2, Gabrielle Couchy2, Quentin Bayard2, Eric Letouzé2, Nathalie Ganne-Carrié4, Christophe Moreno5, Abderrahim Oussalah6, Cyrille Féray7, Jean Frédéric Blanc8, Bruno Clément9, Patrick Hillon10, Jérôme Boursier11, Valérie Paradis12, Julien Calderaro13, Viviane Gnemmi14, Jean-Charles Nault4, Jean-Louis Guéant15, Jacques Devière5, Isabelle Archambeaud16, Carole Vitellius11, Bruno Turlin9, Jean-Pierre Bronowicki17, Thierry Gustot18, Angela Sutton19, Marianne Ziol20, Pierre Nahon4, Jessica Zucman-Rossi21. 1. 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. 2. Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France. 3. Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Radiation Oncology, Peking University Third Hospital, Beijing, China. 4. 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. 5. 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. 6. 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. 7. Centre Hépato-Biliaire, Université Paris-Saclay, Paul Brousse Hospital, Assistance-Publique Hôpitaux de Paris, Paris, France. 8. Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France; Research in Translational Oncology, BaRITOn, Bordeaux, France. 9. 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. 10. University of Bourgogne-Franche Comté, Dijon, France; INSERM U1231, Lipids, Nutrition, Cancer, University Hospital, Dijon, France; Department of Hepatogastroenterology, University Hospital, Dijon, France. 11. 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. 12. Department of Pathology, Hôpital Beaujon, Assistance-Publique Hôpitaux de Paris, Clichy, France. 13. 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. 14. University of Lille, CNRS, Inserm, CHU Lille, Pathology Department, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France. 15. 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. 16. Institut des Maladies de l'Appareil Digestif, Hôtel-Dieu, Nantes, France. 17. 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. 18. 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. 19. 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. 20. 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. 21. 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: jessica.zucman-rossi@inserm.fr.
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 × 10-6) 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 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). 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 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). 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.
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 × 10-6) 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 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). 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 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). 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.
Authors: Sofia Zanotti; Gina F Boot; Mairene Coto-Llerena; John Gallon; Gabriel F Hess; Savas D Soysal; Otto Kollmar; Charlotte K Y Ng; Salvatore Piscuoglio Journal: Front Med (Lausanne) Date: 2022-06-24
Authors: Antonio Gil-Gómez; Ángela Rojas; María R García-Lozano; Rocío Muñoz-Hernández; Rocío Gallego-Durán; Douglas Maya-Miles; Rocío Montero-Vallejo; Sheila Gato; Javier Gallego; Rubén Francés; Germán Soriano; Javier Ampuero; Manuel Romero-Gómez Journal: Int J Mol Sci Date: 2022-10-06 Impact factor: 6.208