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

• Published in: Molecular genetics and genomics : MGG Vol. 298; no. 3; pp. 721 - 733
• Main Authors: Pires, Sara Ferreira, de Barros, Juliana Sobral, da Costa, Silvia Souza, de Oliveira Scliar, Marília, Van Helvoort Lengert, André, Boldrini, Érica, da Silva, Sandra Regina Morini, Tasic, Ljubica, Vidal, Daniel Onofre, Krepischi, Ana Cristina Victorino, Maschietto, Mariana
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2023; Springer Nature B.V
• Subjects: Animal Genetics and Genomics; Biochemistry; Biomedical and Life Sciences; Bone cancer; Bone growth; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Bone remodeling; CpG islands; CpG Islands - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methylation; DNA Methylation - genetics; DNA repair; DNA sequencing; Epigenesis, Genetic; Epigenetics; Genetic diversity; Genomic instability; Histones; Human Genetics; Humans; Inflammation; Life Sciences; Microbial Genetics and Genomics; MicroRNAs; Mixed Function Oxygenases - genetics; Morphogenesis; Original Article; Osteosarcoma; Osteosarcoma - genetics; Osteosarcoma - pathology; Pax6 protein; Phenotypes; Plant Genetics and Genomics; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - genetics; Puberty; Runx3 protein; Sarcoma; Signal transduction; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; Wnt protein; DNA methylation; Mutations; DNMT; TET; Osteosarcoma; Copy-number alterations
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-023-02010-8

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.