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DNA METHYLATION AS A KEY EPIGENETICS PLAYER FOR HEPATOBLASTOMA STRATIFICATION
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  • Maria Rivas*,
  • Talita Aguiar*,
  • Gustavo Fernandes,
  • Luiz Caires-Júnior,
  • Ernesto Goulart,
  • Kayque Telles-Silva,
  • Mariana Maschietto,
  • Monica Cypriano,
  • Silvia Toledo,
  • Dirce Carraro,
  • Isabela Werneck,
  • Cecilia Da Costa,
  • Carla Rosenberg,
  • Ana Krepischi
Maria Rivas*
Institute of Biosciences, University of São Paulo
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Talita Aguiar*
Institute of Biosciences, University of Sao Paulo
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Gustavo Fernandes
Institute of Biosciences, University of Sao Paulo
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Luiz Caires-Júnior
Institute of Biosciences, University of São Paulo
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Ernesto Goulart
Institute of Biosciences, University of São Paulo
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Kayque Telles-Silva
Institute of Biosciences, University of São Paulo
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Mariana Maschietto
Boldrini Children's Hospital
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Monica Cypriano
Institute of Pediatric Oncology
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Silvia Toledo
Genetics Laboratory, Pediatric Oncology Institute GRAACC/UNIFESP
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Dirce Carraro
A. C. Camargo Cancer Center
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Isabela Werneck
Rede D’OR-São Luiz
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Cecilia Da Costa
A.C.Camargo Cancer Center
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Carla Rosenberg
Institute of Biosciences, University of Sao Paulo
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Ana Krepischi
Institute of Biosciences, University of Sao Paulo
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Abstract

Background: Hepatoblastoma (HB) is a rare embryonal liver tumor occurring in the pediatric population, and although intrinsic biological differences between tumors can impact HBs prognosis, few groups have studied this aspect. Given the crescent relevance of epigenetic mechanisms in the genesis and progression of these tumors, we aim to classify HB samples according to the different stages of liver development as well as DNA methylation machinery. Procedures: Using bioinformatics tools, we evaluate the expression of 24 genes associated with epigenetics and stages of hepatocyte differentiation as well as global DNA methylation to propose a stratification model for HB. Results: Based on the gene expression profiles of DNA methylation machinery and hepatocyte differentiation markers, HBs were clustered into three groups. Besides reinforcing the molecular heterogeneity of these embryonal tumors, our data propose that a panel of 13 genes can be used for HB stratification (TET1, TET2, TET3, DNMT1, DNMT3A, UHRF1, ALB, CYP3A4, TDO2, UGT1A1, AFP, HNF4A, and FOXA2). DNA methylation machinery exerts a key role in the characterization of HBs, directly reflected in diverse DNA methylation content. Moreover, we suggest that the group of HBs presenting similarity with differentiated livers, such as upregulation of mature hepatocyte markers, decreased expression of DNA methylation enzymes and higher global methylation levels are associated with a worse prognosis. Conclusions: HBs are heterogeneous tumors and our findings point out the role of the epigenetic machinery in the samples characterization, suggesting the need of new stratification system for patients with HBs.