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Cancer is linked to changes in the 'Dark Matter' of the genome: Study

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Peeyush Ghalot
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(Image Courtesy: - Hindustan Times)

A new study from the Dana-Farber Cancer Institute sheds light on the riddle, revealing signs that may link mutations to epigenetic alterations and suggest to possible therapeutic targets for those born with certain genetic variants. Many portions of the human genome's non-coding region are important regulators of gene function. However, the link between non-coding mutations and the risk of cancer has remained a mystery. This has prompted its own set of issues for cancer researchers: if mutations in coding areas lead cells to produce defective proteins, what happens when mutations in non-coding regions occur? What role does a mutation in the genome's hinterlands — areas devoid of genes — play in cancer? Given the importance of non-coding regions in gene regulation, scientists have speculated that mutations in these areas disrupt gene function in ways that promote cancer. However, research after study has demonstrated that this is not the case, leaving the biological impact of non-coding mutations a mystery. For the first time, a pervasive biological mechanism by which non-coding mutations influence cancer risk has been discovered. It also paves the way for therapies that, by disrupting that mechanism, can lower the risk of certain cancers in at-risk people. Studies have identified a massive number of mutations across the genome that could be involved in cancer. Understanding the biology of how these changes enhance cancer risk has proven difficult.  Investigators use genome-wide association studies, or GWASs, to find inherited, or germline, mutations that increase a person's risk of developing cancer. Researchers collect blood samples from tens or hundreds of thousands of people and scan their genomes for mutations or other variations that are more common in cancer patients than in the general population. These tests have found thousands of mutations, but only a small percentage of them are in coding regions of the genome that are relatively easy to link to cancer. One example is breast cancer. Gusev and Grishin tried a different, more fundamental approach after that route became increasingly uninformative. Rather than starting with the assumption that non-coding mutations affect gene expression, they investigated how they alter their home environment, specifically whether they affect the coiling of DNA in their immediate vicinity. If a mutation causes illness, it will almost certainly be too modest to detect at the level of gene expression, but it may not be so at the level of local epigenetics. It's like if prior research tried to figure out how a brush fire in California may impact the weather in Colorado, but Gusev and Grishin wanted to investigate how it affected the slope where it started. The researchers used this method to build a database of mutations that can now be linked to cancer risk via a biological mechanism. The information can be used to kickstart research into medications that target that process and reduce a person's chance of acquiring specific malignancies.

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