Research Papers:
BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease
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Abstract
Abderrahim Oussalah1,2,*, Patrice Hodonou Avogbe1,*, Erwan Guyot3, Céline Chery1,2, Rosa-Maria Guéant-Rodriguez1,2, Nathalie Ganne-Carrié4,5, Aurélie Cobat6,7, Darius Moradpour8, Bertrand Nalpas9, Francesco Negro10, Thierry Poynard11, Stanislas Pol9,12, Pierre-Yves Bochud13, Laurent Abel6,7,14, Hélène Jeulin15, Evelyne Schvoerer15, Nicodème Chabi16, Emile Amouzou17, Ambaliou Sanni16, Hélène Barraud18, Pierre Rouyer1, Thomas Josse2, Laetitia Goffinet1, Jean-Louis Jouve19, Anne Minello19, Claire Bonithon-Kopp19, Gérard Thiefin20, Vincent Di Martino21, Michel Doffoël22, Carine Richou21, Jean-Jacques Raab23, Patrick Hillon19, Jean-Pierre Bronowicki1,18, Jean-Louis Guéant1,2, for the CiRCE Study Group
1INSERM, U954, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
2Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
3Biochemistry Unit, Jean Verdier Hospital, APHP, Bondy, France and University Paris 13-UFR SMBH/INSERM, Bobigny, France
4Liver Unit and Liver biobank CRB des Hôpitaux Universitaires Paris-Seine-Saint-Denis BB-0033-00027, Jean Verdier Hospital, APHP, Bondy, France
5INSERM, U1162, Génomique fonctionnelle des Tumeurs solides, Paris, France
6Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
7Paris Descartes University, Imagine Institute, Paris, France
8Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Switzerland
9Département d'Hépatologie, Hôpital Cochin (AP-HP), Université Paris Descartes, Paris, France
10Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland
11Université Pierre et Marie Curie, Service d'Hépato-gastroentérologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France
12INSERM UMS20, Institut Pasteur, Paris, France
13Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Switzerland
14St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, NY, USA
15Virology Laboratory, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France
16Laboratory of Biochemistry and Molecular Biology, University of Cotonou, Cotonou, Benin
17Laboratory of Biochemistry and Nutrition, Lomé, University of Kara, Togo
18Department of Hepato-Gastroenterology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
19INSERM, U866 and INSERM, CIE 01, University Hospital of Dijon, University of Burgundy, Dijon, France
20Department of Hepato-Gastroenterology, Reims University Hospital, Reims, France
21Department of Hepatology, University Hospital of Besançon, Besançon, France
22Department of Hepato-Gastroenterology, University Hospital of Strasbourg, Strasbourg, France
23Regional Hospital of Metz, Metz, France
*These authors have contributed equally to this work
Correspondence to:
Jean-Louis Guéant, email: [email protected]
Keywords: DNA repair genes, hepatocellular carcinoma, BRIP1, hepatitis B virus, hepatitis C virus
Received: May 23, 2016 Accepted: July 19, 2016 Published: August 17, 2016
ABSTRACT
The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10–4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 ‘AAA’ haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19–3.39); false discovery rate (FDR)-P=1.31×10–2]. In the Derivation#2 study, results were confirmed for the BRIP1 ‘GGG’ haplotype [OR, 0.53 (0.36–0.79); FDR-P=3.90×10–3]. In both Validation#1 and #2 studies, BRIP1 ‘AAA’ haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09–2.68); FDR-P=7.30×10–2; and OR, 6.45 (4.17–9.99); FDR-P=2.33×10–19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.
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