Global DNA Methylation Differences Involving Germline Structural Variation Impact Gene Expression in Pediatric Brain Tumors

Authors

Fengju Chen
Yiqun Zhang
Wei Li
Fritz J Sedlazeck
Lanlan Shen
Chad J Creighton

Language

English

Publication Date

5-21-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-60110-y

PMID

40399292

PMCID

PMC12095544

PubMedCentral® Posted Date

5-21-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, DNA Methylation, Brain Neoplasms, Child, CpG Islands, Gene Expression Regulation, Neoplastic, Male, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Child, Preschool, Genomic Structural Variation, MutS Homolog 2 Protein, Adolescent, Germ Cells, Cancer genomics, Gene regulation, CNS cancer, Methylation analysis, Epigenomics

Published Open-Access

yes

Recommended Citation

Chen, Fengju; Zhang, Yiqun; Li, Wei; et al., "Global DNA Methylation Differences Involving Germline Structural Variation Impact Gene Expression in Pediatric Brain Tumors" (2025). Children’s Nutrition Research Center Staff Publications. 261.
https://digitalcommons.library.tmc.edu/staff_pub/261