Molecular signatures associated with HCV-induced hepatocellular carcinoma and liver metastasis.

Valeria De Giorgi,Maria Lina Tornesello,Ena Wang,Francesco Izzo,Francesco M Marincola,Franco M Buonaguro,Luigi Buonaguro,Andrea Worschech,Niyaz Ahmed

doi:10.1371/journal.pone.0056153

Abstract

Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV) infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis.ConclusionsA diagnostic molecular signature complementing conventional pathologic assessment was identified.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world [1,2,3]
Genes Differentially Expressed among Distinct Tissues The gene expression profile- of tissue samples from the various groups (HCV-related HCC, non-HCC counterpart, metastases, non-metastatic counterpart and controls from healthy donors) were compared by unsupervised analysis
The HCC and the metastatic samples prevalently clustered into distinct groups, based on differences in their patterns of gene expression (Figure2A)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world [1,2,3]. As for other cancers, the etiology of HCC is multifactorial and progresses through multiple stages [4]. This multistep process may be divided into chronic liver injury, inflammation, cell death, cirrhosis, regeneration, DNA damage, dysplasia and HCC. Different lesions have been considered pre-neoplastic in regard to the development of HCC. The principal risk factor for the development of HCC is hepatitis B virus (HBV) [7,8], followed by hepatitis C virus (HCV) infection [9]. HCCs are more prevalent in men than in women and the incidence increases with age

Methods

Results

Discussion

Conclusion