Oncotarget

Research Papers: Immunology:

HCV-related liver and lymphoproliferative diseases: association with polymorphisms of IL28B and TLR2

Valli De Re _, Mariangela De Zorzi, Laura Caggiari, Gianfranco Lauletta, Maria Lina Tornesello, Elisa Fognani, Marta Miorin, Vito Racanelli, Luca Quartuccio, Laura Gragnani, Sabino Russi, Fabio Pavone, Michela Ghersetti, Elena Garlatti Costa, Pietro Casarin, Riccardo Bomben, Cesare Mazzaro, Giancarlo Basaglia, Massimiliano Berretta, Emanuela Vaccher, Francesco Izzo, Franco Maria Buonaguro, Salvatore De Vita, Anna Linda Zignego, Paolo De Paoli and Riccardo Dolcetti

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Oncotarget. 2016; 7:37487-37497. https://doi.org/10.18632/oncotarget.9303

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Abstract

Valli De Re1,*, Mariangela De Zorzi1,*, Laura Caggiari1, Gianfranco Lauletta2, Maria Lina Tornesello3, Elisa Fognani4, Marta Miorin5, Vito Racanelli6, Luca Quartuccio7, Laura Gragnani4, Sabino Russi2, Fabio Pavone2, Michela Ghersetti8, Elena Garlatti Costa8, Pietro Casarin8, Riccardo Bomben9, Cesare Mazzaro9, Giancarlo Basaglia10, Massimiliano Berretta11, Emanuela Vaccher11, Francesco Izzo12, Franco Maria Buonaguro3, Salvatore De Vita7, Anna Linda Zignego4, Paolo De Paoli13 and Riccardo Dolcetti14,15

1 Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy

2 Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy

3 Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy

4 Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

5 Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy

6 Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy

7 Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy

8 Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy

9 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy

10 Microbiology-Immunology and Virology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy

11 Medical Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy

12 Hepatobiliary Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy

13 Scientific Directorate, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy

14 Cancer Bio-Immunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy

15 University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia

* These authors have equally contributed to this study as first authors

Correspondence to:

Valli De Re, email:

Keywords: HCV, TLR2, IL28B, HCC, NHL, Immunology and Microbiology Section, Immune response, Immunity

Received: February 12, 2016 Accepted: April 19, 2016 Published: May 11, 2016

Abstract

To explore the relationship between innate immunity and hepatitis C Virus (HCV) in determining the risk of cirrhosis (CIR), hepatocellular carcinoma (HCC), mixed cryoglobulinemia syndrome (MCS) and non-Hodgkin lymphoma (NHL), we investigated the impact of the toll-like receptor-2 (TLR2) and interleukin-28B (IL28B) genetic variants. TLR2 -174 del variant was associated with TLR2 expression and with specific downstream molecules that drive the expression of different interleukins; rs12979860 Il28B was important in response to interferon-treatment and in spontaneous clearance of HCV. The risk for liver and lymphoproliferative diseases in HCV progression was clarified by stratifying 862 HCV-positive patients into groups based on liver (CIR, HCC) and lymphoproliferative HCV-related diseases (MCS, NHL) and compared with chronic HCV (CHC) infection. Analysis of TLR2-IL28B haplotypes showed an association of wild type haplotype with the lymphoproliferative diseases (OR 1.77, p = 0.029) and a slight increase in HCV viral load (HR 1.38, p = 0.054). Wild type haplotype (TLR2 ins/ins- IL28B C/C) was also found associated with older age in patients with an hepatic diseases (in CIR and in HCC p = 0.038 and p = 0.020, respectively) supporting an effect of innate immunity in the liver disease progression. TLR2 and IL28B polymorphisms in combination showed a role in the control of HCV viral load and different HCV disease progression.


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