Global DNA methylation differences involving germline structural variation impact gene expression in pediatric brain tumors

Fengju Chen, Yiqun Zhang, Wei Li, Fritz J. Sedlazeck, Lanlan Shen and Chad J. Creighton ()
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Fengju Chen: Baylor College of Medicine
Yiqun Zhang: Baylor College of Medicine
Wei Li: University of California
Fritz J. Sedlazeck: Baylor College of Medicine
Lanlan Shen: Baylor College of Medicine
Chad J. Creighton: Baylor College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The extent of genetic variation and its influence on gene expression across multiple tissue and cellular contexts is still being characterized, with germline Structural Variants (SVs) being historically understudied. DNA methylation also represents a component of normal germline variation across individuals. Here, we combine germline SVs (by short-read sequencing) with tumor DNA methylation across 1292 pediatric brain tumor patients. For thousands of methylation probes for CpG Islands (CGIs) or enhancers, rare and common SV breakpoints upstream or downstream associate with differential methylation in tumors spanning various histologic types, a significant subset involving genes with SV-associated differential expression. Cancer predisposition genes involving SV-associated differential methylation and expression include MSH2, RSPA, and PALB2. SV breakpoints falling within CGIs or histone marks H3K36me3 or H3K9me3 associate with differential CGI methylation. Genes with SVs and CGI methylation associated with patient survival include POLD4. Our results capture a class of normal phenotypic variation having disease implications.

Date: 2025
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DOI: 10.1038/s41467-025-60110-y

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