Maria Rivas1, Talita Aguiar2, Gustavo Fernandes1, Renan Lemes1, Luiz Caires-Júnior1, Ernesto Goulart1, Kayque Telles-Silva1, Mariana Maschietto3, Monica Cypriano4, Silvia de Toledo4, Dirce Carraro5, Isabela da Cunha6, Cecilia da Costa7, Carla Rosenberg1, Ana Krepischi8. 1. Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil. 2. Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil; Department of Urology - NYU Grossman School of Medicine, New York City, NY, USA. 3. Research Center, Boldrini Children's Hospital, Campinas, Brazil. 4. Department of Pediatrics, Adolescent and Child with Cancer Support Group (GRAACC), Federal University of São Paulo, SP, Brazil. 5. International Center for Research, A. C. Camargo Cancer Center, SP, Brazil. 6. Pathology Department, Rede D'OR-São Luiz, SP, Brazil. 7. Department of Pediatric Oncology, A. C. Camargo Cancer Center, SP, Brazil. 8. Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil. Electronic address: ana.krepischi@ib.usp.br.
Abstract
BACKGROUND: Hepatoblastoma (HB) is a rare embryonal liver tumor of children. Although intrinsic biological differences between tumors can affect prognosis, few groups have studied these differences. Given the recent increased attention to epigenetic mechanisms in the genesis and progression of these tumors, we aimed to classify HB samples according to the stages of liver development and DNA methylation machinery. BASIC PROCEDURES: We evaluated the expression of 24 genes associated with DNA methylation and stages of hepatocyte differentiation and global DNA methylation. Using bioinformatics tools and expression data, we propose a stratification model for HB. MAIN FINDINGS: Tumors clustered into three groups that presented specific gene expression profiles of the panel of DNA methylation enzymes and hepatocyte differentiation markers. In addition to reinforcing these embryonal tumors' molecular heterogeneity, we propose that a panel of 13 genes can stratify HBs (TET1, TET2, TET3, DNMT1, DNMT3A, UHRF1, ALB, CYP3A4, TDO2, UGT1A1, AFP, HNF4A, and FOXA2). DNA methylation machinery participates in the characterization of HBs, directly reflected in diverse DNA methylation content. The data suggested that a subset of HBs were similar to differentiated livers, with upregulation of mature hepatocyte markers, decreased expression of DNA methylation enzymes, and higher global methylation levels; these findings might predict worse outcomes. CONCLUSIONS: HBs are heterogeneous tumors. Despite using a small cohort of 21 HB samples, our findings reinforce that DNA methylation is a robust biomarker for this tumor type.
BACKGROUND: Hepatoblastoma (HB) is a rare embryonal liver tumor of children. Although intrinsic biological differences between tumors can affect prognosis, few groups have studied these differences. Given the recent increased attention to epigenetic mechanisms in the genesis and progression of these tumors, we aimed to classify HB samples according to the stages of liver development and DNA methylation machinery. BASIC PROCEDURES: We evaluated the expression of 24 genes associated with DNA methylation and stages of hepatocyte differentiation and global DNA methylation. Using bioinformatics tools and expression data, we propose a stratification model for HB. MAIN FINDINGS: Tumors clustered into three groups that presented specific gene expression profiles of the panel of DNA methylation enzymes and hepatocyte differentiation markers. In addition to reinforcing these embryonal tumors' molecular heterogeneity, we propose that a panel of 13 genes can stratify HBs (TET1, TET2, TET3, DNMT1, DNMT3A, UHRF1, ALB, CYP3A4, TDO2, UGT1A1, AFP, HNF4A, and FOXA2). DNA methylation machinery participates in the characterization of HBs, directly reflected in diverse DNA methylation content. The data suggested that a subset of HBs were similar to differentiated livers, with upregulation of mature hepatocyte markers, decreased expression of DNA methylation enzymes, and higher global methylation levels; these findings might predict worse outcomes. CONCLUSIONS: HBs are heterogeneous tumors. Despite using a small cohort of 21 HB samples, our findings reinforce that DNA methylation is a robust biomarker for this tumor type.