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.

PubMed Disclaimer

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.

Cited by

NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.
Wang Y, Liu X, Zuo X, Wang C, Zhang Z, Zhang H, Zeng T, Chen S, Liu M, Chen H, Song Q, Li Q, Yang C, Le Y, Xing J, Zhang H, An J, Jia W, Kang L, Zhang H, Xie H, Ye J, Wu T, He F, Zhang X, Li Y, Zhou G. Wang Y, et al. Cell Genom. 2024 May 8;4(5):100550. doi: 10.1016/j.xgen.2024.100550. Epub 2024 May 1. Cell Genom. 2024. PMID: 38697125 Free PMC article.
Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.
Nischalke HD, Schmalz F, Buch S, Fischer J, Möller C, Matz-Soja M, Krämer B, Langhans B, Klüners A, Soyka M, Stickel F, Nattermann J, Berg T, Strassburg CP, Lutz P. Nischalke HD, et al. Int J Mol Sci. 2022 Dec 5;23(23):15353. doi: 10.3390/ijms232315353. Int J Mol Sci. 2022. PMID: 36499681 Free PMC article.
Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.
Fu Q, Dai H, Shen S, He Y, Zheng S, Jiang H, Gu P, Sun M, Zhu X, Xu K, Yang T. Fu Q, et al. Diabetologia. 2025 Jan;68(1):116-127. doi: 10.1007/s00125-024-06291-5. Epub 2024 Oct 19. Diabetologia. 2025. PMID: 39425782
Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.
Hassan MM, Li D, Han Y, Byun J, Hatia RI, Long E, Choi J, Kelley RK, Cleary SP, Lok AS, Bracci P, Permuth JB, Bucur R, Yuan JM, Singal AG, Jalal PK, Ghobrial RM, Santella RM, Kono Y, Shah DP, Nguyen MH, Liu G, Parikh ND, Kim R, Wu HC, El-Serag H, Chang P, Li Y, Chun YS, Lee SS, Gu J, Hawk E, Sun R, Huff C, Rashid A, Amin HM, Beretta L, Wolff RA, Antwi SO, Patt Y, Hwang LY, Klein AP, Zhang K, Schmidt MA, White DL, Goss JA, Khaderi SA, Marrero JA, Cigarroa FG, Shah PK, Kaseb AO, Roberts LR, Amos CI. Hassan MM, et al. Hepatology. 2024 Jul 1;80(1):87-101. doi: 10.1097/HEP.0000000000000800. Epub 2024 Feb 20. Hepatology. 2024. PMID: 38381705 Free PMC article.
COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.
Cai MN, Chen DM, Chen XR, Gu YR, Liao CH, Xiao LX, Wang JL, Lin BL, Huang YH, Lian YF. Cai MN, et al. Cell Oncol (Dordr). 2024 Oct;47(5):1897-1910. doi: 10.1007/s13402-024-00972-4. Epub 2024 Jul 30. Cell Oncol (Dordr). 2024. PMID: 39080215

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical