Abstract 4914: A novel integrative network study identifies key genes and pathways in the progression of Hepatitis C virus induced hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality in the world. Incidence of hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) has been increasing in the United States and Europe during recent years. Although HCV-associated HCC shares many pathological characteristics with other types of HCC, the molecular mechanisms underlying its progression remain elusive. To investigate the underlying pathology, we developed a systematic approach to identify deregulated biological networks in HCC by integrating gene expression profiles with high-throughput protein-protein interaction data. This integrative approach to searching for deregulated networks during each pathological stage is different from typical search of common pathway resources like Gene Ontology or KEGG biochemical pathways. It has at least two advantages: 1) a high throughput protein interaction network covers more genes; and 2) the resulting network gives gene interaction information, which provides a simpler framework to explore the functional associations between genes and generate new biological hypotheses. By comparing sets of consecutive pathological stages, we identified four networks in five groups of samples corresponding to normal, cirrhosis, dysplasia, early HCC and advanced HCC. The functional annotation of each network demonstrates a high degree of consistency with current knowledge of HCC. By assembling these functions into a modular map, we were able to depict the stepwise pathways that are dysregulated in HCV-induced hepatocarcinogenesis. Additionally, these networks enable us to identify important genes and pathways by developmental stage, such as LCK signaling pathways in cirrhosis, MMP genes and TIMP genes in dysplastic liver, and CDC2-mediated cell cycle signaling in early and advanced HCC. CDC2 (alternative symbol CDK1), a regulatory gene in cell cycle control, is particularly interesting due to its topological position in temporally deregulated networks. Our study uncovers a temporal spectrum of functional deregulation, and prioritizes key genes and pathways in the progression of HCV induced HCC. These findings present a wealth of information for further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4914. doi:10.1158/1538-7445.AM2011-4914