INTRODUCTION
Hepatoblastoma (HB) is a rare liver tumor occurring in childhood1, hypothetically arising from hepatocyte precursors2. There is a reported global trend towards an increasing incidence of HB over the last years 3 which could be caused by the rising of premature children, associated with low birthweight, a known risk factor for HB 4. The overall 5-year survival rate of children with HB is 70% 5,6; however, patients who do not respond to standard treatment have very low survival 7–10. HB are heterogeneous with several histologic types 2, frequently displaying combinations of epithelial, stromal, mesenchymal and/or undifferentiated cells11.Despite this clinical heterogeneity, a few recurrent genetic lesions were reported in HBs, that present the lowest reported burden of somatic mutations 12. Epigenetic mechanisms seem to be crucial factors to be considered in the genesis and progression of this tumor. In our previous work13, the evaluation of HB methylomes disclosed a lower level of DNA methylation is non-repetitive sequences compared to non-tumoral livers, a finding corroborated by others14, in addition to hypermethylation in CpG islands mapped in genes associated with tumor suppression, lipid metabolism, and liver differentiation. Moreover, we unraveled changes in gene expression of the epigenetic machinery in HBs that support a model of an active demethylation process in this tumor, probably during the early stages of liver development 15. HB is an embryonal tumor, for which the main hypothesis of origin proposes that cancer arises from a failure of cell differentiation, leading to the rupture of the normal process of organ development 16. Therefore, some childhood tumors could mimic the activity of embryonic cells; as an example, the α-fetoprotein, only produced by the fetal liver, is increased in most HBs 17. Although intrinsic biological differences between tumors can impact HBs prognosis, few groups have studied this aspect. Here, we focus on the model of the origin of embryonal tumors to classify HB samples according to the different stages of liver development, based on gene expression analysis of markers of hepatocyte differentiation as well as enzymes of the DNA methylation machinery. Using these data, we provide a framework to stratify HBs, correlating the molecular biomarkers with clinical features.