DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations

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Maschietto, Mariana ^[1] ; Rodrigues, Tatiane Cristina ^[2] ; Kashiwabara, Andre Yoshiaki ^[3] ; Souza de Araujo, Erica Sara ^[4] ; Marques Aguiar, Talita Ferreira ^[4] ; Lima da Costa, Cecilia Maria ^[5] ; da Cunha, Isabela Werneck ^[6] ; Vasques, Luciana dos Reis ^[2] ; Cypriano, Monica ^[7] ; Brentani, Helena ^[8] ; Caminada de Toledo, Silvia Regina ^[7] ; Pearson, Peter Lees ^[2] ; Carraro, Dirce Maria ^[4] ; Rosenberg, Carla ^[2] ; Krepischi, Ana C. V. ^[2]

Afiliação do(s) autor(es)

^[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Campinas, SP - Brazil

^[2] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo - Brazil

^[3] Univ Tecnol Fed Parana, Campus Cornelio Procopio, Curitiba, Parana - Brazil

^[4] AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo - Brazil

^[5] AC Camargo Canc Ctr, Dept Pediat Oncol, Sao Paulo - Brazil

^[6] AC Camargo Canc Ctr, Dept Pathol, Sao Paulo - Brazil

^[7] Univ Fed Sao Paulo, Pediat Oncol Inst GRAACC, Dept Pediat, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ONCOTARGET; v. 8, n. 58, p. 97871-97889, NOV 17 2017.
• Citações Web of Science: 0

Resumo

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 similar to 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. (AU)

• Processo FAPESP: 11/24007-9 - Anomalias genéticas e epigenéticas no tumor embrionário hepatoblastoma
• Beneficiário: Tatiane Cristina Rodrigues
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 09/00898-1 - Desequilíbrios genômicos submicroscópicos em quadros clínicos específicos de anomalias congênitas e deficiência mental
• Beneficiário: Carla Rosenberg
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/06281-7 - Investigação da regulação epigenética em tumores sólidos pediátricos
• Beneficiário: Mariana Camargo Maschietto
• Linha de fomento: Bolsas no Brasil - Apoio a Jovens Pesquisadores
• Processo FAPESP: 16/04785-0 - Estudo de mutações somáticas identificadas em sequenciamento de exoma de hepatoblastoma
• Beneficiário: Talita Ferreira Marques Aguiar
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs