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

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

. 2022 Jan;23(1):161-171.

doi: 10.1016/S1470-2045(21)00603-3. Epub 2021 Dec 11.

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

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; GENTHEP Consortium; Marianne Ziol²⁰, Pierre Nahon⁴, Jessica Zucman-Rossi²¹

Collaborators, Affiliations

Collaborators

GENTHEP Consortium:
Clément Meiller, Qian Cao, Théo Z Hirsch, Sandra Rebouissou, Delphine Degré, Lukas Otero Sanchez, Nicolas Rosewick, Eric Quertinmont, Mireille Desille-Dugast, Muriel François-Vié, Cécile Moins, Emmanuelle Leteurtre, Guillaume Lassailly, Massih Ningarhari, Emmanuel Boleslawski, Vanessa Cottet

Affiliations

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.

PMID: 34902334
DOI: 10.1016/S1470-2045(21)00603-3

Free article

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

Eric Trépo et al. Lancet Oncol. 2022 Jan.

Free article

. 2022 Jan;23(1):161-171.

doi: 10.1016/S1470-2045(21)00603-3. Epub 2021 Dec 11.

Authors

Collaborators

GENTHEP Consortium:
Clément Meiller, Qian Cao, Théo Z Hirsch, Sandra Rebouissou, Delphine Degré, Lukas Otero Sanchez, Nicolas Rosewick, Eric Quertinmont, Mireille Desille-Dugast, Muriel François-Vié, Cécile Moins, Emmanuelle Leteurtre, Guillaume Lassailly, Massih Ningarhari, Emmanuel Boleslawski, Vanessa Cottet

Affiliations

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.

PMID: 34902334
DOI: 10.1016/S1470-2045(21)00603-3

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.

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Conflict of interest statement

Declaration of interests ET received research support from Gilead. NG-C received honoraria from Roche, Gilead, and Ipsen, and support for travel and attending meetings from Gilead. CM received research support from Gilead; consulting fees from Gilead, AbbVie, Novartis, Surrozen, and Julius Clinical; support for travel and attending meetings from Gilead and AbbVie; honoraria from Bayer and Astellas; and acted as a scientific advisor to Gilead and Novartis. J-CN received research support from Bayer and Ipsen. J-PB received consulting fees from Bayer, Roche, and Ipsen; honoraria from Bayer, Ipsen, and Roche; support for travel and attending meetings from Bayer, Ipsen, and Roche; and acted as a scientific advisor to Roche. TG received research support from Gilead, honoraria from AbbVie, and acted as a scientific advisor to GoLiver Therapeutics and Promethera Biosciences. PN received research support from Bristol Myers Squibb, Eisai, and Roche; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Gilead, Eisai, Roche, Ipsen, and Exact Science; honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Gilead, Eisai, Roche, Ipsen, and Exact Science; support for travel and attending meetings from Ipsen and Roche; and acted as a scientific advisor to AstraZeneca, Bayer, Bristol Myers Squibb, Gilead, Eisai, Roche, Ipsen, and Exact Science. All other authors declare no competing interests.

Comment in

Rs708113 in WNT3A-WNT9A and hepatocellular carcinoma risk.
Stickel F, Hampe J. Stickel F, et al. Lancet Oncol. 2022 Jan;23(1):14-16. doi: 10.1016/S1470-2045(21)00663-X. Epub 2021 Dec 11. Lancet Oncol. 2022. PMID: 34902337 No abstract available.
GWAS reveals variants for alcohol-related hepatocellular carcinoma.
Hindson J. Hindson J. Nat Rev Gastroenterol Hepatol. 2022 Feb;19(2):79. doi: 10.1038/s41575-022-00575-0. Nat Rev Gastroenterol Hepatol. 2022. PMID: 35017673 No abstract available.

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

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

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