Mechanism linking mutations in the ‘dark matter’ genome to cancer: a study | health

A research study by the Dana-Farber Cancer Institute sheds light on this conundrum, providing clues that may link mutations to genetic changes, and may point to potential drug targets to reduce the risk of people born with certain genetic mutations.

Several sections of the noncoding region in the human genome play a major role in regulating gene activity. But the relationship between non-coding mutations and cancer The danger was a mystery.

For many years, the human genome was viewed as a book of life interspersed with sections of great rhetoric and the economy of expression with vast expanses of chatter. The read sections contained the code for making cell proteins. Other regions, accounting for about 90% of the total genomedismissed as “junk DNA,” has no clear purpose.

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Research has taught scientists otherwise. Far from being a useless filler, many non-coding sections have been shown to play a major 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 defective proteins, what do mutations in noncoding regions do? How might a mutation in the most remote regions of the genome – in regions without genes – contribute to cancer?

Given that non-coding regions are involved in gene regulation, the researchers hypothesized, of course, that mutations in these regions damage gene activity in ways that lead to cancer. However, study after study has found that this is generally not the case, leaving the biological impact of non-coding mutations to a mystery.

think local

In a new research paper in Nature Genetics, Dana-Farber investigators provide an answer. They did so with the scientific equivalent of thinking locally – narrowing their search 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 how tightly the DNA is wrapped at those sites. This, in turn, affects how open those sites 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 for treatments that, by disrupting this mechanism, can reduce the likelihood that people at risk will develop some types of cancer.

“Studies have identified a huge number of mutations across the genome potentially implicated in cancer,” says Alexander Joseph, Ph.D. of Dana-Farber, the Eli and Edith L. Broad Institute and Brigham and Women’s Hospital, who co-authored the paper with Dennis Grishin of Dana-Farber. , Ph.D. “The challenge was to understand the biology by which these differences increase cancer risk. Our study revealed an important part of that biology.”

Does the mutation change the expression?

To identify inherited mutations, or germs, that increase a person’s risk of developing cancer, researchers conduct what are known as genome-wide association studies, or GWASs. In these, researchers collect blood samples from tens or hundreds of thousands of people and check their genomes for mutations or other differences that are more common in people with cancer than in those without the disease.

Tests such as these have yielded 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 one example. “More than 300 mutations associated with an increased risk of disease have been identified,” Josef says. “Less than 10% of them are actually in the genes. The rest are in ‘desert’ areas, and it’s not clear how they affect disease risk.”

To try to make this connection, the researchers combined two sets of data: one, GWAS data that shows mutations in a specific type of cancer; And second, data on another genomic trait 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 data sets, in a process called colocalization, researchers can determine whether mutations correspond to a rise or a decrease in the activity of those genes. If such a relationship exists, it would help explain how non-coding mutations could lead to cancer.

Despite the massive investment in this type of research, positioning studies have shown very few such correspondences. Joseph notes that “the vast number of mutations identified by GWASs have been found to have no colocalization gene at all”. “For the most part, non-coding mutations associated with cancer risk do not interfere with changes in gene expression [activity] documented in public data sets”.

Finding close to home

As this path became increasingly ill-fated, Joseph and Grishin attempted another, more fundamental approach. Rather than starting with the hypothesis that non-coding mutations might affect gene expression, they asked how they alter their home environment — whether it affects DNA winding in its immediate vicinity.

“We hypothesized that if you look at the effect of these mutations on local epigenetics — specifically, whether they cause nearby DNA to be more tightly or loosely wound — we would be able to detect changes that would not be evident in expression on the basis of studies,” Joseph relates.

Their reasoning: “If a mutation has an effect on disease, it’s possible that that effect will be too subtle to be picked up at the gene expression level but may not be too subtle to be picked up at the local epigenetics level — what’s going on right around the corner,” Josef says.

It is as if previous studies sought to understand how the California Brush Fire affected the weather in Colorado, while Joseph and Greshin wanted to see its effect on the slope of the hill where it began.

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

The results came in stark contrast to those obtained from coloration studies. “We found that while most non-coding mutations have no effect on gene expression, most of them have an effect on local epigenetic regulation,” Joseph says. “We now have a basic biological explanation for how the vast majority of high-risk mutations are associated with cancer, while this mechanism was previously unknown.”

Using this approach, the researchers created a database of mutations that can now be linked to cancer risk through a known biological mechanism. The database could serve as a starting point for research into drugs that, by targeting that mechanism, could reduce an individual’s risk of developing some types of cancer.

“If we know, for example, that there is a certain transcription factor [a protein involved in switching genes on and off] One of these mutations is linked to cancer, and we may be able to develop drugs that target this factor, thus reducing the likelihood that people born with this mutation will develop cancer,” says Joseph.

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