DNA methylation patterns suggest the involvement of DNMT3B and TET1 in osteosarcoma development

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Pires, Sara Ferreira ; de Barros, Juliana Sobral ; da Costa, Silvia Souza ; Scliar, Marilia de Oliveira ; Lengert, Andre Van Helvoort ; Boldrini, Erica ; Morini da Silva, Sandra Regina ; Tasic, Ljubica ; Vidal, Daniel Onofre ; Victorino Krepischi, Ana Cristina ; Maschietto, Mariana

• Tipo de documento: Artigo Científico
• Fonte: Molecular Genetics and Genomics; v. 298, n. 3, p. 13-pg., 2023-04-05.

Resumo

DNA methylation may be involved in the development of osteosarcomas. Osteosarcomas commonly arise during the bone growth and remodeling in puberty, making it plausible to infer the involvement of epigenetic alterations in their development. As a highly studied epigenetic mechanism, we investigated DNA methylation and related genetic variants in 28 primary osteosarcomas aiming to identify deregulated driver alterations. Methylation and genomic data were obtained using the Illumina HM450K beadchips and the TruSight One sequencing panel, respectively. Aberrant DNA methylation was spread throughout the osteosarcomas genomes. We identified 3146 differentially methylated CpGs comparing osteosarcomas and bone tissue samples, with high methylation heterogeneity, global hypomethylation and focal hypermethylation at CpG islands. Differentially methylated regions (DMR) were detected in 585 loci (319 hypomethylated and 266 hypermethylated), mapped to the promoter regions of 350 genes. These DMR genes were enriched for biological processes related to skeletal system morphogenesis, proliferation, inflammatory response, and signal transduction. Both methylation and expression data were validated in independent groups of cases. Six tumor suppressor genes harbored deletions or promoter hypermethylation (DLEC1, GJB2, HIC1, MIR149, PAX6, and WNT5A), and four oncogenes presented gains or hypomethylation (ASPSCR1, NOTCH4, PRDM16, and RUNX3). Our analysis also revealed hypomethylation at 6p22, a region that contains several histone genes. Copy-number changes in DNMT3B (gain) and TET1 (loss), as well as overexpression of DNMT3B in osteosarcomas provide a possible explanation for the observed phenotype of CpG island hypermethylation. While the detected open-sea hypomethylation likely contributes to the well-known osteosarcoma genomic instability, enriched CpG island hypermethylation suggests an underlying mechanism possibly driven by overexpression of DNMT3B likely resulting in silencing of tumor suppressors and DNA repair genes. (AU)

• Processo FAPESP: 15/06281-7 - Investigação da regulação epigenética em tumores sólidos pediátricos
• Beneficiário: Mariana Camargo Maschietto
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• Processo FAPESP: 18/06510-4 - Aplicação de Ressonância Magnética Nuclear (RMN) em metabolômica e metabonômica de doenças humanas
• Beneficiário: Ljubica Tasic
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/24069-3 - Do biomonitoramento ao reconhecimento de assinaturas do exposoma humano visando antecipar riscos para uma saúde contínua
• Beneficiário: Fernando Barbosa Júnior
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/10250-7 - Investigação da regulação epigenética em tumores sólidos pediátricos
• Beneficiário: Mariana Camargo Maschietto
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores