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Jul 24, 2014

Decoding Noncoding DNA's Role in Colorectal Cancer

  • Scientists have been alert to genetic drivers of cancer that are embedded in the transcriptome, which consists of DNA’s coding regions. Beyond the transcriptome, in the wider genome, lurk additional drivers. They are, most likely, elements that regulate gene expression—or rather, being faulty, dysregulate gene expression.

    Expanding the search for cancer drivers into the wider genome, effectively sifting through noncoding stretches of DNA, a team of scientists centered at the University of Geneva (UNIGE) performed an RNA sequencing analysis of 103 matched tumor and normal colon mucosa colorectal cancer (CRC) samples. According to the scientists, theirs was the first study of this scale to examine the noncoding genome of cancer patients.

    The UNIGE team and its collaborators described the study July 23 in Nature, in an article entitled, “Putative cis-regulatory drivers in colorectal cancer.” The scientists reported that they were able to identify two kinds of noncoding mutations that have an impact on the development of colorectal cancer.

    They found hereditary regulatory variants that are not active in healthy tissue, but are activated in tumors and seem to contribute to cancer progression. In addition, they identified effects of acquired mutations on the regulation of gene expression that affect the genesis and progression of colorectal tumors.

    In particular, the researchers detected 71 genes with significantly higher allele-specific expression (ASE) somatic event rates, which they defined as genes with allelic dysregulation (GADs), as well as 376 genes with tumor-specific germline cis-regulatory variants.

    “Both categories demonstrate characteristics that support their role as putative cancer drivers,” wrote the study’s authors. “This gives us access to putative noncoding somatic and germline CRC drivers on an unprecedented scale.”

    “In addition, tumor-specific cis-eQTLs [expression quantitative trait loci] reveal a new category of variants that are likely to contribute to cancer besides predisposing alleles and somatic mutations,” the authors continued. “It is likely that some of the predisposing variants discovered via GWAS are in fact germline drivers.”

    The head of the research team, Emmanouil Dermitzakis, Ph.D., Louis-Jeantet Professor of Genetics in UNIGE’s faculty of medicine, noted that the methodology used here to evaluate colorectal cancer could also be applied “to understand the genetic basis of all sorts of cancers.”

    “The elements responsible for the development and progression of cancers located in the noncoding genome are as important as those found in the coding regions of the genome,” added Halit Ongen, D.Phil., a postdoctoral researcher at UNIGE and the lead author of the study. “Therefore, analyzing genetic factors in our whole genome, and not only in the coding regions as it was done before, gives us a much more comprehensive knowledge of the genetics behind colorectal cancer.”


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