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Int J Cancer. 2019 Feb 1;144(3):533-544. doi: 10.1002/ijc.31910. Epub 2018 Nov 9.

PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases.

Author information

1
Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
2
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium.
3
Liver unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
4
Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
5
Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China.
6
Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France.
7
CHU de Bordeaux, Department of Neurology, Bordeaux, France.
8
University of Lille, Institut National de la Santé et de la Recherche Médicale, CHU Lille, Institut Pasteur de Lille, Lille, France.
9
Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, Bordeaux, France.
10
Service de Pathologie, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.
11
Service d'anatomopathologie, Hôpital Henri Mondor, Créteil.
12
Université Paris Est Créteil, Inserm U955, Team 18, Institut Mondor de Recherche Biomédicale, France.
13
Service de chirurgie digestive, Hôpital Henri Mondor, Créteil.
14
Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, France.
15
Service Hépato-Gastroentérologie et oncologie digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France.
16
Laboratoire de biochimie, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
17
INSERM U1148 LVTS, UFR SMBH, Université Paris 13, PRES Paris Sorbonne Cité, Bobigny, France.
18
Centre de Ressources Biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
19
Hôpital Europeen Georges Pompidou, Paris, France.

Abstract

Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3-rs738409, TM6SF2-rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 [CI95%:1.16-2.40], p = 0.005; OR = 1.45 [CI95%:1.08-1.94], p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4-rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 [CI95%:2.52-6.06], p = 1.14E-09; OR = 1.79 [CI95%:1.25-2.56], p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 [CI95%:1.22-3.92], p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3-rs738409 and TM6SF2-rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.

KEYWORDS:

STAT4; cirrhosis; liver cancer; predisposition; single nucleotide polymorphisms

PMID:
30289982
DOI:
10.1002/ijc.31910

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