The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival.

TitleThe DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival.
Publication TypeJournal Article
Year of Publication2024
AuthorsChen, F, Zhang, Y, Shen, L, Creighton, CJ
JournalNat Commun
Volume15
Issue1
Pagination6775
Date Published2024 Aug 08
ISSN2041-1723
KeywordsBrain Neoplasms, Child, CpG Islands, Cyclin-Dependent Kinase Inhibitor p16, DNA Methylation, Epigenome, Female, Gene Expression Regulation, Neoplastic, Humans, Male, N-Myc Proto-Oncogene Protein, Proto-Oncogene Proteins c-myc, Telomerase, X-linked Nuclear Protein
Abstract

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.

DOI10.1038/s41467-024-51276-y
Alternate JournalNat Commun
PubMed ID39117669
PubMed Central IDPMC11310301
Grant ListP30 CA125123 / CA / NCI NIH HHS / United States
CA125123 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) /

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