Produção Nacional
DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations
2016; Impact Journals LLC; Volume: 8; Issue: 58 Linguagem: Inglês
10.18632/oncotarget.14208
ISSN1949-2553
AutoresMariana Maschietto, Tatiane Rodrigues, André Yoshiaki Kashiwabara, Érica Sara Souza de Araújo, Talita Ferreira Marques Aguiar, Cecília Maria Lima da Costa, Isabela Werneck da Cunha, L.R. Vasques, Mônica Cypriano, Helena Brentani, Sílvia Regina Caminada de Toledo, P. Pearson, Dirce Maria Carraro, Carla Rosenberg, Ana Cristina Victorino Krepischi,
Tópico(s)Cancer-related gene regulation
Resumo// Mariana Maschietto 1, * , Tatiane Cristina Rodrigues 2, * , André Yoshiaki Kashiwabara 3 , Érica Sara Souza de Araujo 4 , Talita Ferreira Marques Aguiar 4 , Cecilia Maria Lima da Costa 5 , Isabela Werneck da Cunha 6 , Luciana dos Reis Vasques 2 , Monica Cypriano 7 , Helena Brentani 8 , Silvia Regina Caminada de Toledo 7 , Peter Lees Pearson 2 , Dirce Maria Carraro 4 , Carla Rosenberg 2 , Ana C.V. Krepischi 2 1 Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil 2 Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil 3 Universidade Tecnológica Federal do Paraná, Campus Cornélio Procópio, Paraná, Brazil 4 International Research Center, A. C. Camargo Cancer Center, São Paulo, Brazil 5 Department of Pediatric Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil 6 Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil 7 Department of Pediatrics, Pediatric Oncology Institute (GRAACC), Federal University of São Paulo, São Paulo, Brazil 8 Department 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: ana.krepischi@ib.usp.br 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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