Development of hepatocellular carcinoma (HCC) is a multi-step progressive process in which a healthy liver transforms into cancerous tissue. Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage, serving as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become “immortal”) by inactivating growth control genes and reactivating telomerase reverse transcriptase gene. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during HCC development in patients with liver cirrhosis; however, the accompanying transcriptional changes are virtually unknown. This study describes genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Starting with a strong support of the hypothesis that in vitro senescent HCC clones are alike in vivo cirrhosis cells, and in vitro immortal HCC cells are alike in vivo HCC hepatocytes using microarray data analysis methods; we determined differentially expressed genes and deregulated biological mechanisms during senescence escape and immortalization. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Since an epigenetic player gene, ATAD2, came forward as one of the hepatocellular immortality signature test genes in senescence escape processes, we also investigated roles of epigenetic regulatory genes in hepatocellular carcinogenesis. Bioinformatics analyzes on cirrhosis and HCC as well as dysplasia and normal liver samples using a comprehensive list of epigenetic regulatory genes revealed several transcriptionally deregulated epigenetic regulatory mechanisms during liver carcinogenesis. However, we could not detect any mutational differences in N-terminal tail encoding DNA sequences of histone variants. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.