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

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dc.citation.issue58
dc.citation.volume8
dc.contributor.authorMaschietto, Mariana
dc.contributor.authorRodrigues, Tatiane Cristina
dc.contributor.authorKashiwabara, Andre Yoshiaki
dc.contributor.authorSouza de Araujo, Erica Sara
dc.contributor.authorMarques Aguiar, Talita Ferreira
dc.contributor.authorLima da Costa, Cecilia Maria
dc.contributor.authorda Cunha, Isabela Werneck
dc.contributor.authorVasques, Luciana dos Reis
dc.contributor.authorCypriano, Monica [UNIFESP]
dc.contributor.authorBrentani, Helena
dc.contributor.authorCaminada de Toledo, Silvia Regina [UNIFESP]
dc.contributor.authorPearson, Peter Lees
dc.contributor.authorCarraro, Dirce Maria
dc.contributor.authorRosenberg, Carla
dc.contributor.authorKrepischi, Ana C. V.
dc.coverageOrchard Park
dc.date.accessioned2020-09-01T13:21:16Z
dc.date.available2020-09-01T13:21:16Z
dc.date.issued2017
dc.description.abstractHepatoblastomas 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.en
dc.description.affiliationBrazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Campinas, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo, Brazil
dc.description.affiliationUniv Tecnol Fed Parana, Campus Cornelio Procopio, Curitiba, Parana, Brazil
dc.description.affiliationAC Camargo Canc Ctr, Int Res Ctr, Sao Paulo, Brazil
dc.description.affiliationAC Camargo Canc Ctr, Dept Pediat Oncol, Sao Paulo, Brazil
dc.description.affiliationAC Camargo Canc Ctr, Dept Pathol, Sao Paulo, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Pediat Oncol Inst GRAACC, Dept Pediat, Sao Paulo, Brazil
dc.description.affiliationUniv Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Pediat Oncol Inst GRAACC, Dept Pediat, Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFAPESP
dc.description.sponsorshipCNPq
dc.description.sponsorshipIDFAPESP: 2009/00898-1
dc.description.sponsorshipIDFAPESP: 2011/24007-9
dc.description.sponsorshipIDFAPESP: 2013/08028-1
dc.description.sponsorshipIDFAPESP: 2016/04785-0
dc.description.sponsorshipIDFAPESP: 2015/06281-7
dc.description.sponsorshipIDCNPq: 470446_2013-7
dc.format.extent97871-97889
dc.identifierhttp://dx.doi.org/10.18632/oncotarget.14208
dc.identifier.citationOncotarget. Orchard Park, v. 8, n. 58, p. 97871-97889, 2017.
dc.identifier.doi10.18632/oncotarget.14208
dc.identifier.fileWOS000419392300015.pdf
dc.identifier.issn1949-2553
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/58165
dc.identifier.wosWOS:000419392300015
dc.language.isoeng
dc.publisherImpact Journals Llc
dc.relation.ispartofOncotarget
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectDNA methylationen
dc.subjectembryonal tumoren
dc.subjecthypomethylationen
dc.subjectcell differentiation arresten
dc.subjecthepatoblastomaen
dc.titleDNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterationsen
dc.typeinfo:eu-repo/semantics/article
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