Research Papers:
DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations
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Abstract
Mariana Maschietto1,*, Tatiane Cristina Rodrigues2,*, André Yoshiaki Kashiwabara3, Érica Sara Souza de Araujo4, Talita Ferreira Marques Aguiar4, Cecilia Maria Lima da Costa5, Isabela Werneck da Cunha6, Luciana dos Reis Vasques2, Monica Cypriano7, Helena Brentani8, Silvia Regina Caminada de Toledo7, Peter Lees Pearson2, Dirce Maria Carraro4, Carla Rosenberg2, Ana C.V. Krepischi2
1Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
2Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
3Universidade Tecnológica Federal do Paraná, Campus Cornélio Procópio, Paraná, Brazil
4International Research Center, A. C. Camargo Cancer Center, São Paulo, Brazil
5Department of Pediatric Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil
6Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil
7Department of Pediatrics, Pediatric Oncology Institute (GRAACC), Federal University of São Paulo, São Paulo, Brazil
8Department of Psychiatry, School of Medicine, University of São Paulo, São Paulo, Brazil
*These authors have contributed equally to this work
Correspondence to:
Ana C.V. Krepischi, email: [email protected]
Keywords: DNA methylation; embryonal tumor; hypomethylation; cell differentiation arrest; hepatoblastoma
Received: March 08, 2016 Accepted: December 05, 2016 Published: December 25, 2016
ABSTRACT
Hepatoblastomas are uncommon embryonal liver tumors accounting for approximately 80% of childhood hepatic cancer. We hypothesized that epigenetic changes, including DNA methylation, could be relevant to hepatoblastoma onset. The methylomes of eight matched hepatoblastomas and non-tumoral liver tissues were characterized, and data were validated in an independent group (11 hepatoblastomas). In comparison to differentiated livers, hepatoblastomas exhibited a widespread and non-stochastic pattern of global low-level hypomethylation. The analysis revealed 1,359 differentially methylated CpG sites (DMSs) between hepatoblastomas and control livers, which are associated with 765 genes. Hypomethylation was detected in hepatoblastomas for ~58% of the DMSs with enrichment at intergenic sites, and most of the hypermethylated CpGs were located in CpG islands. Functional analyses revealed enrichment in signaling pathways involved in metabolism, negative regulation of cell differentiation, liver development, cancer, and Wnt signaling pathway. Strikingly, an important overlap was observed between the 1,359 DMSs and the CpG sites reported to exhibit methylation changes through liver development (p<0.0001), with similar patterns of methylation in both hepatoblastomas and fetal livers compared to adult livers. Overall, our results suggest an arrest at early stages of liver cell differentiation, in line with the hypothesis that hepatoblastoma ontogeny involves the disruption of liver development. This genome-wide methylation dysfunction, taken together with a relatively small number of driver genetic mutations reported for both adult and pediatric liver cancers, shed light on the relevance of epigenetic mechanisms for hepatic tumorigenesis.
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