Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study - Archive ouverte HAL
Article Dans Une Revue Lancet Oncology Année : 2022

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

1 ULB - Université libre de Bruxelles
2 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
3 PKUPH - People's Hospital of Peking University
4 Hôpital Avicenne [AP-HP]
5 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
6 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
7 Hôpital Paul Brousse
8 CHU Bordeaux
9 BaRITOn - Bordeaux Research In Translational Oncology [Bordeaux]
10 NuMeCan - Nutrition, Métabolismes et Cancer
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
12 CRB Santé - Centre de Ressources Biologiques Santé
13 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
14 CHU Dijon
15 HIFIH - Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques
16 CHU Angers - Centre Hospitalier Universitaire d'Angers
17 Hôpital Beaujon [AP-HP]
18 IMRB - Institut Mondor de Recherche Biomédicale
19 Hôpital Henri Mondor
20 CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
21 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
22 Institut des Maladies de l'Appareil Digestif
23 Hôtel-Dieu de Nantes
24 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
25 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
26 HUP2SD - Hôpitaux Universitaires Paris Seine-Saint-Denis [Sevran]
27 HEGP - Hôpital Européen Georges Pompidou [APHP]
C. Feray
  • Fonction : Auteur

Résumé

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 (pandlt;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.
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Dates et versions

hal-03718253 , version 1 (16-09-2022)

Identifiants

Citer

E. Trepo, S Caruso, J. Yang, S Imbeaud, G Couchy, et al.. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. Lancet Oncology, 2022, 23 (1), pp.161-171. ⟨10.1016/S1470-2045(21)00603-3⟩. ⟨hal-03718253⟩
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