Accepted Manuscript Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis Arige Tarhuni, Erwan Guyot, Pierre Rufat, Angela Sutton, Valérie Bourcier, Véronique Grando, Nathalie Ganne-Carrié, Marianne Ziol, Nathalie Charnaux, Michel Beaugrand, Richard Moreau, Jean-Claude Trinchet, Abdellah Mansouri, Pierre Nahon PII: DOI: Reference:
S0168-8278(14)00264-5 http://dx.doi.org/10.1016/j.jhep.2014.04.011 JHEPAT 5113
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
26 September 2013 3 March 2014 7 April 2014
Please cite this article as: Tarhuni, A., Guyot, E., Rufat, P., Sutton, A., Bourcier, V., Grando, V., Ganne-Carrié, N., Ziol, M., Charnaux, N., Beaugrand, M., Moreau, R., Trinchet, J-C., Mansouri, A., Nahon, P., Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep.2014.04.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis Short title: Polymorphisms in cytokines and liver cancer Arige Tarhuni1, Erwan Guyot2,3, Pierre Rufat4, Angela Sutton2,3, Valérie Bourcier2,5, Véronique Grando 2,5, Nathalie Ganne-Carrié2,5, Marianne Ziol6,7, Nathalie Charnaux1,2, Michel Beaugrand2,5, Richard Moreau1, Jean-Claude Trinchet2,5,6, Abdellah Mansouri1 and Pierre Nahon1,2,5. 1
INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris
7, Paris, France ; 2University Paris 13-UFR SMBH / INSERM U698, Bobigny, France; 3
Biochemistry Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France;
4
Biostatistics Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; 5Liver Unit, Jean
Verdier Hospital, APHP, University Paris 13, Bondy, France ;
6
Liver Biobank « CRB
Maladies du foie », Jean Verdier Hospital, APHP, University Paris 13, Bondy, France; 7
Pathology Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
Keywords: inflammation; cytokines; polymorphisms; liver cancer. Correspondence: Pierre Nahon, Service d’Hépato-Gastroentérologie, Hôpital Jean Verdier, 93140 Bondy, France Tel: 33-1-48-02-62-80 Fax: 33-1-48-02-62-02 Email: [email protected]
Electronic word count: 4988, Figures: 3, Tables: 4, Suppl Tables: 5, Suppl Figure: 3.
Abbreviations: HCC: hepatocellular carcinoma; HCV: hepatitis C virus; IL: Interleukin; SNP: single nucleotide polymorphism; SVR: sustained virological response; TNF: tumour necrosis factor.
Disclosure of potential conflicts of interest: No conflicts of interest exist.
Grants: This work was supported in part by grants from the Société Nationale Française de Gastro-Entérologie (SNFGE).
1
Abstract Background & Aims: Genetic polymorphisms modulate the expression of proinflammatory cytokines. We prospectively assessed the influence of 6 single nucleotide polymorphisms (SNPs) in TNFα, IL-6 and IL1β genes on the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis. Methods: TNFα (G-238A, C-863A, G-308A), IL-6 (C-174G) and IL1β (C-31T, C-511T) SNPs were assessed in 232 alcoholics and 253 HCV-infected patients with biopsy-proven cirrhosis, prospectively followed up and screened for HCC. Their influence on HCC development was assessed using the Kaplan-Meier method. Results: These variants did not influence the risk of HCC in alcoholic patients. Conversely, two variants influenced the risk of HCC occurrence in patients with HCV-related cirrhosis, namely the TNFα-308 (A) allele (HR=2.4 [1.6-3.7], log-rank
S0168-8278(14)00264-5 http://dx.doi.org/10.1016/j.jhep.2014.04.011 JHEPAT 5113
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
26 September 2013 3 March 2014 7 April 2014
Please cite this article as: Tarhuni, A., Guyot, E., Rufat, P., Sutton, A., Bourcier, V., Grando, V., Ganne-Carrié, N., Ziol, M., Charnaux, N., Beaugrand, M., Moreau, R., Trinchet, J-C., Mansouri, A., Nahon, P., Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep.2014.04.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis Short title: Polymorphisms in cytokines and liver cancer Arige Tarhuni1, Erwan Guyot2,3, Pierre Rufat4, Angela Sutton2,3, Valérie Bourcier2,5, Véronique Grando 2,5, Nathalie Ganne-Carrié2,5, Marianne Ziol6,7, Nathalie Charnaux1,2, Michel Beaugrand2,5, Richard Moreau1, Jean-Claude Trinchet2,5,6, Abdellah Mansouri1 and Pierre Nahon1,2,5. 1
INSERM, U773, Centre de Recherche Biomédicale, Bichat Beaujon CRB3, University Paris
7, Paris, France ; 2University Paris 13-UFR SMBH / INSERM U698, Bobigny, France; 3
Biochemistry Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France;
4
Biostatistics Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; 5Liver Unit, Jean
Verdier Hospital, APHP, University Paris 13, Bondy, France ;
6
Liver Biobank « CRB
Maladies du foie », Jean Verdier Hospital, APHP, University Paris 13, Bondy, France; 7
Pathology Unit, Jean Verdier Hospital, APHP, University Paris 13, Bondy, France.
Keywords: inflammation; cytokines; polymorphisms; liver cancer. Correspondence: Pierre Nahon, Service d’Hépato-Gastroentérologie, Hôpital Jean Verdier, 93140 Bondy, France Tel: 33-1-48-02-62-80 Fax: 33-1-48-02-62-02 Email: [email protected]
Electronic word count: 4988, Figures: 3, Tables: 4, Suppl Tables: 5, Suppl Figure: 3.
Abbreviations: HCC: hepatocellular carcinoma; HCV: hepatitis C virus; IL: Interleukin; SNP: single nucleotide polymorphism; SVR: sustained virological response; TNF: tumour necrosis factor.
Disclosure of potential conflicts of interest: No conflicts of interest exist.
Grants: This work was supported in part by grants from the Société Nationale Française de Gastro-Entérologie (SNFGE).
1
Abstract Background & Aims: Genetic polymorphisms modulate the expression of proinflammatory cytokines. We prospectively assessed the influence of 6 single nucleotide polymorphisms (SNPs) in TNFα, IL-6 and IL1β genes on the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis. Methods: TNFα (G-238A, C-863A, G-308A), IL-6 (C-174G) and IL1β (C-31T, C-511T) SNPs were assessed in 232 alcoholics and 253 HCV-infected patients with biopsy-proven cirrhosis, prospectively followed up and screened for HCC. Their influence on HCC development was assessed using the Kaplan-Meier method. Results: These variants did not influence the risk of HCC in alcoholic patients. Conversely, two variants influenced the risk of HCC occurrence in patients with HCV-related cirrhosis, namely the TNFα-308 (A) allele (HR=2.4 [1.6-3.7], log-rank
