Epigenetic mechanisms in liver tumors: expression modulation of epigenetic gene regulators and gene expression analysis by RNAseq in hepatoblastoma.

Abstract

Liver tumors are rare in children and represent only 1 - 4% of all pediatric solid tumors. While in adults hepatocellular carcinoma is prevalent, the most common liver cancer in children is hepatoblastoma. Based on very early age and histological feature that recapitulates stages of liver organogenesis, hepatoblastomas are considered embryonal tumors. Because of its rarity, the molecular mechanisms underlying the development of this tumor type are still little explored, so the prognosis of patients with metastatic and advanced tumor stage remains low and children who survive often face serious effects after aggressive chemotherapy. The traditional model of cancer development postulates the accumulation of genetic changes over time; however, pediatric tumors have a short time frame for the occurrence of such changes, a fact that is reflected in the low frequency of mutations compared to adult tumors. In recent years, the paradigm mediated tumorigenesis synergy between different mutations has been expanded to incorporate epigenetic regulation mechanisms of genomic expression. The dialogue between genetic and epigenetic processes is also the core of normal processes of embryogenesis and development, such as cell differentiation and organogenesis. Therefore, the epigenetic acquires additional significance in the context of cancers in children and, in particular, embryonic tumors.The main hypothesis of embryonal tumors origin requires a development from precursor cells of the organ, due to a blockage in normal cell differentiation process. In a previous study from our group, the study of hepatoblastomas metiloma revealed hypomethylation between fetal and differentiated liver, two main biological pathways affected by epigenetic modifications, one associated with tumorigenesis and the other related to different stages of liver differentiation. Thus, this project is based in the assumption that hypomethylation in precursor liver cells (hepatoblasts) would be the main epigenetic mechanism for the development of hepatoblastomas. Therefore, the main object of study will explore the role of methylation in the origin of hepatic tumors and, and, in particular, hepatoblastomas. (AU)