A multi-institutional team led by researchers at Baylor College of Medicine says that genomic structural variation is an unappreciated mechanism involved in altering DNA methylation. They published their study (“Global impact of somatic structural variation on the DNA methylome of human cancers”) in Genome Biology.

The scientists brought together data from whole genome sequencing, gene expression, and DNA methylation from more than 1,400 human cancers. They reported that structural variations consistently altered DNA methylation affecting hundreds of genes, overall reducing the global level of DNA methylation across cancers.

“Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored,” the investigators wrote.

“By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1,400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant  breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs.

“Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration.

“Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.”

“Genomic structural variations occur when a piece of DNA that is in one part of the genome is moved to another part of the genome, which shows up as a break point in the sequence. Therefore, when sequencing a DNA segment, one may find two pieces of DNA from other regions fused together, which disrupts the genetic instructions encoded in DNA,” said corresponding author Chad Creighton, PhD, associate professor of medicine and co-director of cancer bioinformatics of the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine.

In this study, Creighton and his colleagues looked at the effect genomic structural variation has on both DNA methylation and gene expression in human cancers. They analyzed data from two different large science consortiums, the Cancer Genome Atlas and the Pancancer Analysis of Whole Genomes. These data include molecular alterations across the entire genome; that is on both protein-coding genes and on their regulatory regions, for thousands of cancers. The datasets include the same information from noncancerous tissues for comparison.

Working with so many patient samples gave more statistical power to the researchers’ analyses and enabled them to find new genes that might be involved in cancer, according to Creighton, who noted that “this time we had more cases and deeper sequencing than what was previously available.”

In the first part of the study, the researchers discovered that genomic structural variations played a major role in altering DNA methylation in a sizable fraction of cancers. DNA methylation is one way to control gene expression; it’s part of the epigenome, which refers to all the chemical modifications to DNA and associated proteins that regulate the expression of genes within the genome.

“Methylation changes were happening in a non-random way across multiple cancer types,” Creighton continued. “Some of these genes were known before to be linked to cancer, but we also identified genes that were not previously associated with this condition. Some genes may be directly involved in the disease, others might be passengers.”

Overall, structural variation was associated with a global decrease in DNA methylation.

“We know that in cancer the epigenome is altered. In the current study, we found that structural variation is one important mechanism that is altering the epigenome. This was not appreciated before,” Creighton added. “We think this may be one of the first surveys of cancer genomics that shows where these changes in DNA methylation happen and in what types of cancer.”

In the second part of the study, the researchers found that there is variability across cancers in terms of the amount of structural variation present within a given cancer. Some cancers may not be heavily altered while others have widespread structural variation. These findings enabled the researchers to stratify cancers in terms of how much structural variation they have.

This and other analyses told the researchers a lot about what is going on in these cancers. For instance, Creighton and his colleagues found that cancers that have a high level of DNA alterations also tended to have a decrease in immune cell infiltration. This finding may have implications for cancer immunotherapy.

“We think that our study is unique in the sense that we found that structural variation plays a major role not only in introducing mistakes in DNA sequences but also affecting DNA at the epigenetic level,” pointed out Creighton. “We propose that the effect of structural variation on DNA methylation is something to consider when looking for the genetic causes of a cancer.”

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