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.