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

Acyltransferases / genetics Adult Aged Aged, 80 and over Alcohol-Related Disorders / genetics Carcinoma, Hepatocellular / genetics Case-Control Studies Female Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Genotype Humans Liver Neoplasms / genetics Male Middle Aged Phospholipases A2, Calcium-Independent / genetics Polymorphism, Single Nucleotide Wnt Proteins / genetics Wnt3A Protein / genetics Young Adult

Journal

The Lancet. Oncology

ISSN: 1474-5488

Titre abrégé: Lancet Oncol

Pays: England

ID NLM: 100957246

Informations de publication

Date de publication:
01 2022

Historique:

received: 15 08 2021

revised: 03 10 2021

accepted: 15 10 2021

pubmed: 14 12 2021

medline: 25 2 2022

entrez: 13 12 2021

Statut: ppublish

Résumé

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. 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 The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10 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. Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

Sections du résumé

BACKGROUND

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

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

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.

Identifiants

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

pubmed: 34902334

pii: S1470-2045(21)00603-3

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

pii:

doi:

Substances chimiques

WNT3A protein, human 0

WNT9A protein, human 0

Wnt Proteins 0

Wnt3A Protein 0

Acyltransferases EC 2.3.-

adiponutrin, human EC 3.1.1.3

Phospholipases A2, Calcium-Independent EC 3.1.1.4

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

161-171

Investigateurs

Clément Meiller (C)

Qian Cao (Q)

Théo Z Hirsch (TZ)

Sandra Rebouissou (S)

Delphine Degré (D)

Lukas Otero Sanchez (L)

Nicolas Rosewick (N)

Eric Quertinmont (E)

Mireille Desille-Dugast (M)

Muriel François-Vié (M)

Cécile Moins (C)

Emmanuelle Leteurtre (E)

Guillaume Lassailly (G)

Massih Ningarhari (M)

Emmanuel Boleslawski (E)

Vanessa Cottet (V)

Commentaires et corrections

Type : CommentIn

Informations de copyright

Déclaration de conflit d'intérêts

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.