The DNA Methylome of Pediatric Brain Tumors Appears Shaped by Structural Variation and Predicts Survival

Authors

Fengju Chen
Yiqun Zhang
Lanlan Shen
Chad J Creighton

Publication Date

8-8-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-51276-y

PMID

39117669

PMCID

PMC11310301

PubMedCentral® Posted Date

8-8-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, DNA Methylation, Brain Neoplasms, CpG Islands, Child, Gene Expression Regulation, Neoplastic, X-linked Nuclear Protein, Epigenome, Cyclin-Dependent Kinase Inhibitor p16, N-Myc Proto-Oncogene Protein, Proto-Oncogene Proteins c-myc, Male, Telomerase, Female, Cancer genomics, Paediatric cancer, Cancer epigenetics, CNS cancer

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.

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