Primary liver cancer or hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, accounting for an estimated 550,000 deaths per year, representing 10% of all deaths from cancer. In part because of the difficulty of early diagnosis of HCC, less than 1% of patients with HCC are treated with radical, potentially curative treatments such as liver transplantation or surgical resection.
Risk factors for HCC include chronic hepatitis and cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), dietary exposure to fungal aflatoxins, immune-related disorders such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis, and genetic disorders such as hemochromatosis and alpha-1-antitrypsin deficiency. The incidence of HCC in the US has increased by 70% over the past twenty years, due to the increased prevalence of chronic HCV infection. As the prevalence of obesity and obesity-related NASH increases in the US, it is likely that the increased prevalence of NASH-induced cirrhosis will lead to continued increases in the incidence of HCC.
The genetic changes underlying the development and progression of HCC are complex and incompletely understood. The long-term objective of our laboratory is to understand the molecular pathogenesis of HCC and translate new research findings into improvements in prevention, early diagnosis, prognostic prediction, and treatment of HCC. The development, growth and metastasis of cancers depends on the acquisition of a multifaceted malignant phenotype which includes self sufficiency in growth signals, insensitivity to anti-growth signals, limitless replicative potential, increased resistance to apoptosis, the capability for tissue invasion and metastasis, and sustained angiogenesis. In an effort to improve our understanding of the key mechanisms of hepatocellular carcinogenesis, we are employing three complementary approaches to identify and characterize genes involved in the pathogenesis of HCC.
These approaches are:
- Gene expression profiling using high-density oligonucleotide cDNA microarray technology.
- The cloning of the human genomic sites of hepatitis B virus integration to identify the genes that are targeted by integration events.
- The cloning and characterization of genes located in common fragile site regions.