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

Authors: CHEN, FENGJU - Baylor College Of Medicine; ZHANG, YIQUN - Baylor College Of Medicine; SHEN, LANLAN - Children'S Nutrition Research Center (CNRC); CREIGHTON, CHAD - Baylor College Of Medicine

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/2/2024
Publication Date: 8/8/2024
Citation: Chen, F., Zhang, Y., Shen, L., Creighton, C.J. 2024. The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival. Nature Communications. 15. Article 6775. https://doi.org/10.1038/s41467-024-51276-y.
DOI: https://doi.org/10.1038/s41467-024-51276-y

Interpretive Summary: This study investigates how changes in DNA affect cancer, focusing on pediatric brain and central nervous system tumors. Researchers analyzed over 2,400 tumors and discovered that certain DNA changes, called structural variants, can influence how genes are turned on or off and alter DNA markings known as DNA methylation. Key genes like ATRX and CDKN2A, which help prevent tumors, were impacted by these changes. The study also found that DNA changes near genes like MYC and MYCN affected their activity in the tumors. Some of these genetic changes were linked to patient survival, including genes like BCOR, TERT, RCOR2, and PDLIM4. Additionally, DNA changes in tumors that return or worsen could help predict survival. This research helps us understand how DNA changes influence cancer and could lead to better treatments. The findings could also support the USDA's work in agriculture and nutrition by improving our understanding of how DNA changes impact health, potentially leading to better strategies for disease prevention, including cancer, and personalized nutrition plans tailored to an individual’s genetic makeup, which could improve health outcomes.

Technical 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.