Scientists discover mechanism linking genome ‘dark matter’ mutations to cancer

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

Research has taught scientists otherwise. Far from being an unnecessary burden, many non-coding sections have been shown to play a key role in regulating gene activity – turning it up or down as needed. For oncologists, this has raised questions in itself: If mutations in coding regions cause cells to make faulty proteins, what do mutations in non-coding regions do? How does a mutation in the hinterland of the genome—in areas lacking genes—contribute to cancer?

Since non-coding regions are involved in gene regulation, the researchers hypothesized, naturally, that mutations in these areas disrupt gene activity in ways that promote cancer. However, study after study has found that this is generally not the case, leaving the biological impact of non-coding mutations something of a mystery.

Think locally

In a new article in the journal Nature Genetics, Dana-Farber investigators have provided an answer. They did this using the scientific equivalent of local thinking – narrowing the scope of their investigation to the specific DNA in which the non-coding mutations occur. They found that in the overwhelming number of cases examined, such mutations have an epigenetic effect, that is, they change the degree of DNA wrapping at those locations. This, in turn, affects whether these locations are open to binding to other sections of DNA or certain proteins, all of which can influence the activity of genes implicated in cancer.

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

“Studies have identified an enormous number of mutations across the genome that are potentially implicated in cancer,” says Alexander Gusev, PhD, from Dana-Farber, Eli and Edythe L. Broad Institute and Brigham and Women’s Hospital, co-authored the article with Dennis Grishin, PhD, from Dana-Farber. “The challenge has been to understand the biology by which these variations increase the risk of cancer. Our study uncovered an important part of this biology.

Does the mutation change the expression?

To identify inherited or germline mutations that increase the risk of developing cancer, researchers conduct what are called genome-wide association studies, or GWAS. In these, researchers take blood samples from tens or hundreds of thousands of people and analyze their genomes for mutations or other variations that are more common in people with cancer than those without. are not affected by the disease.

These tests revealed thousands of such mutations, but only a small percentage of them are in coding parts of the genome that are relatively easy to link to cancer. Breast cancer is an example. “More than 300 mutations associated with an increased risk of the disease have been identified,” says Gusev. “Less than 10% of them are actually in the genes. The rest are in ‘desert’ regions, and their influence on disease risk is unclear.

To try to make this link, the researchers are putting together two sets of data: first, GWAS data showing mutations in a specific type of cancer; and second, data about another genomic characteristic of this type of cancer, such as an abnormally high or low level of activity in certain genes. By looking for areas of overlap between these datasets, in a process called colocalization, researchers can determine whether mutations correspond to increased or decreased activity of these genes. If such a relationship exists, it would help explain how non-coding mutations can lead to cancer.

Despite massive investment in this type of research, however, collocation studies have revealed very few such matches. “The large number of mutations identified by GWAS have no colocating genes,” Gusev notes. “For the most part, non-coding mutations associated with cancer risk do not overlap with changes in gene expression [activity] documented in public datasets.

Looking closer to home

With this route looking increasingly dim, Gusev and Grishin tried another, more fundamental approach. Instead of assuming that non-coding mutations might influence gene expression, they asked how they alter their home environment – ​​whether they affect DNA winding in their immediate vicinity.

“We hypothesized that if you looked at the effect of these mutations on local epigenetics – specifically, whether they cause nearby DNA to wrap tighter or looser – we would be able to detect changes that would not be evident in the term studies,” Gusev recounts.

Their reasoning: “If a mutation has an effect on disease, that effect will likely be too subtle to capture at the gene expression level, but perhaps not too subtle to capture at the local epigenetics level – that that just happens around the mutation. says Gusev.

It’s as if earlier studies sought to understand how a California bushfire could affect the weather in Colorado, while Gusev and Grishin wanted to see its effect on the hill where it started.

To do this, they performed a different type of overlay study. They took GWAS data on cancer-related mutations and data on epigenetic changes in seven common types of cancer and looked at if – and where – they intersect.

The results contrast sharply with those of colocation studies. “We found that while most non-coding mutations have no effect on gene expression, most of them do impact local epigenetic regulation,” Gusev says. “We now have a basic biological explanation for how the vast majority of cancer risk mutations are potentially linked to cancer, where previously no such mechanism was known.”

Using this approach, the researchers created a database of mutations that can now be linked to cancer risk by a known biological mechanism. The database can serve as a starting point for the search for drugs that, by targeting this mechanism, can reduce the risk of developing certain cancers.

“If we know, for example, that a certain transcription factor [a protein involved in switching genes on and off] binds to one of these cancer-associated mutations, we may be able to develop drugs that target this factor, potentially reducing the likelihood that people born with this mutation will get cancer,” Gusev says.

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