Researchers discover mechanism linking mutations in the ‘dark matter’ of the genome to cancer

For many years, the human genome was viewed as a book of life in which sections of great eloquence and economy of expression were interspersed with vast stretches of gibberish. The legible sections contained the code for making cell proteins; the other regions, representing about 90% of the entire genome, were dismissed as “junk DNA,” having no discernable purpose.

Research has taught scientists otherwise. Far from being useless filler, many non-coding sections have been shown to play a key role in regulating gene activity — increasing or decreasing it as needed. For cancer scientists, this has raised questions of its own: if mutations in coding regions cause cells to make flawed proteins, what do mutations in non-coding regions do? How does a mutation in the hinterlands of the genome — in areas devoid of genes — contribute to cancer?

Given that non-coding regions are involved in gene regulation, researchers have hypothesized, naturally, that mutations in these zones play havoc with gene activity in ways conducive cancer. Study after study, however, has found this generally not to be the case, leaving the biological impact of non-coding mutations something of a mystery.

Thinking locally

In a new paper in the journal Nature Genetics, Dana-Farber investigators provided an answer. They did so by the scientific equivalent of thinking locally — narrowing the scope of their investigation to the specific DNA in which non-coding mutations occur. They found that in the overwhelming number of cases examined, such mutations have an epigenetic effect — that is, they change how tightly the DNA at those locations is wrapped. That, in turn, affects how open those locations are to binding to other sections of DNA or certain proteins, all of which can influence the activity of genes involved in cancer.

The discovery reveals, for the first time, a pervasive biological mechanism by which non-coding mutations can influence cancer risk. It also opens the way to therapies that, by disrupting that mechanism, can reduce at-risk people’s likelihood of developing certain cancers.

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