IDENTIFYING EARLY STEPS IN THE DEVELOPMENT OF HBV ASSOCIATED HCC

Abstract

The hepatitis B virus (HBV), chronically infecting ~360 million people worldwide, accounts for over half of the cases of hepatocellular carcinoma (HCC) and contributes to over 650,000 deaths per year making HCC is the fifth most common and second most deadly form of cancer.1-3 Many genes deregulated by the hepatitis B x-antigen (HBx), the oncogenic protein encoded by HBV, are known drivers of HCC.4,5 The timing of these alterations in the initiation and progression of disease, however, are poorly understood and the treatment options for HCC are extremely limited. Here, RNA-Seq expression data originally from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project were used to compare truly healthy liver tissues, a base-line level often excluded from cancer studies, to both non-tumor and tumor tissues of patients with HBV associated HCC. This illuminated inflammation and immune response process as dysregulated prior to tumor formation followed by disruption of cell cycle and cell survival processes once tumors have arisen. Connecting these processes are UBD, BCL6, METTL24, CHRNA4, and NFKBIZ which putatively serve as crucial early drivers in the progression from HBV infection to the development of HCC and affect the serum level of downstream targets which could serve as biomarkers for earlier disease detection. Differential methylation analysis was also carried out on samples directly from TCGA and the Gene Expression Omnibus (GEO) to determine if the differentially expressed genes were potentially deregulated due to reversible epigenetic alterations. Enriched pathways for differential methylation in non-tumor samples included the immune system and the cell cycle but none of the genes of interest from differential expression analysis were differentially methylated until stage 1 indicating that methylation is involved in the progression of disease and not initiation.