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BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease

2016; Impact Journals LLC; Volume: 8; Issue: 38 Linguagem: Inglês

10.18632/oncotarget.11327

1949-2553

Abderrahim Oussalah, Patrice Hodonou Avogbe, Erwan Guyot, Céline Chery, Rosa‐Maria Guéant‐Rodriguez, Nathalie Ganne–Carrié, Aurélie Cobat, Darius Moradpour, Bertrand Nalpas, Francesco Negro, Thierry Poynard, Stanislas Pol, Pierre‐Yves Bochud, Laurent Abel, Hélène Jeulin, Évelyne Schvoerer, Nicodème Chabi, Emile Amouzou, Ambaliou Sanni, Hélène Barraud, Pierre Rouyer, Thomas Josse, Lætitia Goffinet, Jean–Louis Jouve, Anne Minello, Claire Bonithon‐Kopp, Gérard Thiéfin, Vincent Di Martino, Michel Doffoël, Carine Richou, Jean-Jacques Raab, Patrick Hillon, Jean‐Pierre Bronowicki, Jean‐Louis Guéant,

RNA modifications and cancer

// Abderrahim Oussalah 1, 2, * , Patrice Hodonou Avogbe 1, * , Erwan Guyot 3 , Céline Chery 1, 2 , Rosa-Maria Guéant-Rodriguez 1, 2 , Nathalie Ganne-Carrié 4, 5 , Aurélie Cobat 6, 7 , Darius Moradpour 8 , Bertrand Nalpas 9 , Francesco Negro 10 , Thierry Poynard 11 , Stanislas Pol 9, 12 , Pierre-Yves Bochud 13 , Laurent Abel 6, 7, 14 , Hélène Jeulin 15 , Evelyne Schvoerer 15 , Nicodème Chabi 16 , Emile Amouzou 17 , Ambaliou Sanni 16 , Hélène Barraud 18 , Pierre Rouyer 1 , Thomas Josse 2 , Laetitia Goffinet 1 , Jean-Louis Jouve 19 , Anne Minello 19 , Claire Bonithon-Kopp 19 , Gérard Thiefin 20 , Vincent Di Martino 21 , Michel Doffoël 22 , Carine Richou 21 , Jean-Jacques Raab 23 , Patrick Hillon 19 , Jean-Pierre Bronowicki 1, 18 , Jean-Louis Guéant 1, 2 , for the CiRCE Study Group 1 INSERM, U954, NGERE – Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France 2 Department of Molecular Medicine and Personalized Therapeutics, Department of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France 3 Biochemistry Unit, Jean Verdier Hospital, APHP, Bondy, France and University Paris 13-UFR SMBH/INSERM, Bobigny, France 4 Liver Unit and Liver biobank CRB des Hôpitaux Universitaires Paris-Seine-Saint-Denis BB-0033-00027, Jean Verdier Hospital, APHP, Bondy, France 5 INSERM, U1162, Génomique fonctionnelle des Tumeurs solides, Paris, France 6 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France 7 Paris Descartes University, Imagine Institute, Paris, France 8 Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Switzerland 9 Département d'Hépatologie, Hôpital Cochin (AP-HP), Université Paris Descartes, Paris, France 10 Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland 11 Université Pierre et Marie Curie, Service d'Hépato-gastroentérologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France 12 INSERM UMS20, Institut Pasteur, Paris, France 13 Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Switzerland 14 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, NY, USA 15 Virology Laboratory, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France 16 Laboratory of Biochemistry and Molecular Biology, University of Cotonou, Cotonou, Benin 17 Laboratory of Biochemistry and Nutrition, Lomé, University of Kara, Togo 18 Department of Hepato-Gastroenterology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France 19 INSERM, U866 and INSERM, CIE 01, University Hospital of Dijon, University of Burgundy, Dijon, France 20 Department of Hepato-Gastroenterology, Reims University Hospital, Reims, France 21 Department of Hepatology, University Hospital of Besançon, Besançon, France 22 Department of Hepato-Gastroenterology, University Hospital of Strasbourg, Strasbourg, France 23 Regional Hospital of Metz, Metz, France * These authors have contributed equally to this work Correspondence to: Jean-Louis Guéant, email: jean-louis.gueant@univ-lorraine.fr 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.