A comprehensive picture of genetic variations and their influence on gene expression across multiple tissue and cellular contexts, including human cancers, is still being characterized, with germline Structural Variants (SVs) being historically understudied.
A proper understanding gene expression in cancer is important since this can reveal how the disease begins, develops and potentially how to control it or eliminate it.
Looking to improve our understanding in this field, researchers at Baylor College of Medicine and collaborating institutions, including University of California – Irvine and Rice University, investigated for the first time in cancer the association between two sources of genetic variation: germline or inherited structural variation (SV), which refers to large differences in the DNA sequence, and DNA methylation, which is when genes are turned on or off without altering the DNA code.
The researchers found that germline structural variations influence DNA methylation in various types of brain tumors, which altered the expression of numerous genes.
Based on these finding the team created a catalog of the affected genes. Although many of these gene changes might not play a part in cancer, some seem to be involved in cancer-related roles, including predisposition to the disease and patient survival.
The study results, supported by National Institutes of Health grant, appears in the May 21, 2025 edition of Nature Communications.[1]
“Scientists have learned a great deal about how cancer emerges and develops by studying changes or mutations in individual ‘letters’ of the genetic code. We have taken a different approach by studying how larger variations in the genetic code, known as germline or inherited structural variation, influence gene expression in human cancers,” said corresponding author Chad Creighton, Ph.D., professor of medicine and co-director of cancer bioinformatics at the Dan L Duncan Comprehensive Cancer Center at Baylor.
“Structural variation refers to large differences in the DNA sequence across individuals involving missing, duplicated or switched-around DNA sections. These larger variations can affect how genes are turned on or off, especially when they occur near important control regions of the genome.” Creighton added.
Regulating normal genetic variations
DNA methylation is another way cells regulate normal genetic variation across individuals. In this case, cells regulate their gene activity without changing the genetic code. Known as epigenetics, the mechanism works by adding chemical tags such as methyl groups on DNA. The tags act like a switch that can turn a gene on or off. Previous studies have shown that both Structural Variants and DNA methylation alterations are associated with cancer.
“We analyzed germline Structural Variants and tumor DNA methylation in 1,292 samples from children with brain tumors as provided by the Children’s Brain Tumor Network (CBTN),” Creighton said.
We found that thousands of Structural Variants were linked to differing levels of DNA methylation in the tumors. Some of the differences affected gene enhancers, which regulate the expression of other genes. In many cases, these genetic variants occur near genes known to be involved in cancer predisposition, such as MSH2, RSPA and PALB2. Other genes with Structural Variants and methylation changes were associated with patient survival, including gene POLD4.”
The researchers hope their findings will guide future studies to better understand the landscape of genetic and epigenetic influences in cancer and eventually lead to improved tools for identifying children at risk or tailoring therapies to individual genetic profiles.
Reference
[1] Chen F, Zhang Y, Li W, Sedlazeck FJ, Shen L, Creighton CJ. Global DNA methylation differences involving germline structural variation impact gene expression in pediatric brain tumors. Nat Commun. 2025 May 21;16(1):4713. doi: 10.1038/s41467-025-60110-y. PMID: 40399292; PMCID: PMC12095544.
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