Scientists have for the first time linked mutations located outside of coding genes to changes in tumor gene expression, aiding the development of future diagnostic and therapeutic strategies.
Zhang et al utilized sequencing databases to identify hundreds of mutations in DNA sequences outside of coding genes, paving the way for novel therapeutic avenues to treat cancer. Image Credit: Zhang et al, doi: 10.1038/s41588-018-0091-2.
Cancers develop due to uncontrolled cell growth and division, ultimately leading to the metastatic spread of cancer cells throughout the body, causing mass organ dysfunction.
Pioneering research has indicated that transformation into a cancerous cell is driven by accumulation of mutations in cellular DNA.
Researchers have elucidated the impact of specific mutations within genes and have found that these mutations play an integral role in the hallmarks of cancer. This research has led to the development of many successful therapeutics used in the clinic today.
However, the vast majority of mutations found in cancer cells are found in DNA sequences outside of genes, called noncoding regions. These mutations have been more resistant to interrogation.
Researchers from UC San Diego identified hundreds of mutations in noncoding regions that directly regulate the expression of genes involved in cancer. Their work was published in the journal Nature Genetics.
“Most cancer-related mutations occur in regions of the genome outside of genes, but there are so incredibly many of them that it’s hard to know which are actually relevant and which are merely noise,” said senior author Dr. Trey Ideker, professor at Moores Cancer Center and UC San Diego School of Medicine.
Some attempts at understanding the impact of noncoding mutations have been made using The Cancer Genome Atlas (TCGA), an NIH-founded repository of genome sequencing data from both normal tissues and tumors. However, these efforts have only identified one relevant noncoding mutation.
Ideker and his collaborators succeeded where others couldn’t by adding an extra layer of analysis while utilizing TCGA data.
“The secret sauce was to look for changes in gene expression,” Ideker said.
“Here for the first time we found about 200 mutations in non-coding DNA that are functional in cancer — and that’s about 199 more than we knew before,” he added.
The team validated their findings by modeling the impact of these functional noncoding mutations in cancer cell lines.
They found that these mutations directly impacted the expression of genes that drive hallmarks of cancer, including tumor cell invasion.
“One example that stood out was a noncoding mutation affecting a gene called DAAM1,” said first author Wei Zhang, PhD, a postdoctoral researcher in Ideker’s lab.
“DAAM1 activation makes tumor cells more aggressive, and better able to invade surrounding tissues.”
Their work may help develop novel diagnostic and therapeutic strategies that rely on identifying functional mutations in patient tumors.
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Wei Zhang et al. A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. Nature Genetics, published online April 2, 2018; doi: 10.1038/s41588-018-0091-2
