Impact of IL-28B rs12979860 and rs4803217 Gene Polymorphisms Associated With miRNAs Deregulation on HCV-related Hepatocellular Carcinoma

Summary

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide as well as in Egypt. Despite improvements in HCC therapy, the prognosis for HCC patients remains poor. Today molecular, genomic and epigenomic aberrations in tumors are being deeply investigated. Many biomarkers were associated to HCC onset, and they could be useful for clinicians, but all show some limitations and no one is so early to predict the HCC onset.

It is estimated that 51.5% of HCC cases can be attributed to HCV infection. Moreover, there is a large occult reservoir of HCV caused chronic liver disease in approximately 9 % in the Egyptian with estimated 6 million HCV chronic infections and estimated 150 000 new infections per year. Among them, we have to mention the polymorphism of IL28B gene rs12979860 C/T. and rs 4803217. The IL-28B gene encodes interferon-lambda 3 (IFN-λ3), which belongs to the type III IFN family. IFN-λ interacts with a transmembrane receptor inducing a potent antiviral response. In experimental model of HCV type III IFN was able to inhibit viral replication. IL-28B polymorphisms are linked to the efficiency of the inflammatory process during HCV infection, and to the mechanisms that HCV adopts to escape by innate and adaptive immunity.

During the last years, a number of studies have assessed the association between the IL-28B polymorphisms and risk of HCC and liver cirrhosis (LC) occurrence in various populations; however, results obtained are still inconclusive.

Interestingly, some polymorphisms located at the 3' untranslated region (UTR) of IL28B, e.g. rs 4803217, seem to interfere with the binding of miRNA, to date recognized as important post-transcriptional regulators. In the last years miRNAs acquired a growing relevance as potential biomarkers for several diseases including cancer, and many researches are focusing on understanding their role in cancer.

Thus the objectives of the current proposal are to determine through investigating a cohort of 405 patients, whether IL28B rs12979860 and rs4803217 polymorphisms are associated to the risk of HCC in chronic hepatitis C (CHC) patients and, above all, to identify their role as predictor marker of HCC in CHC, when associated to miRNAs modulation. Data obtained by our work could be helpful in HCC diagnosis, thus leading to the improvement of the patients prognosis. The proposed activities are going to be implemented through a partnership us as Egyptian Liver Research Institute and Hospital (ELRIAH)- Dakhlya- Egypt and Non- Egyptian Partners.

Conditions

• HCV Infection ( Genotype 4)

Interventions

BIOLOGICAL

IL28B Polymorphism

SNP rs12979860 and 4803217 will be determined in whole blood by allelic discrimination using specific probes by real time PCR.

BIOLOGICAL

miRNA quantification

RNAs will be extracted from serum using miRNeasy Mini Kit (Quiagen) according to the manufacturer's instruction. The RNA purity will be assessed by the RNA concentration and quantified by NanoDrop ND-1000 (Nanodrop, United States). cDNA will be obtained by miScript II Reverse Transcription Kits (Quiagen) A Preamplification will be performed using miScript PreAMP PCR Kits (Quiagen) Real Time PCRarray will be done using miScript miRNA PCR Arrays, with SYBR Green PCR Master Mix (Quiagen).

Sponsors & Collaborators

• Dr.Waleed Samir

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

10 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-01-31

Primary Completion

2017-12-31

Countries

• Egypt