How plesiosaurs swam underwater

Researchers are discovering mechanisms that link mutations in the “dark matter” of the genome to cancer

For many years, the human genome was seen as a book of life where parts of great eloquence and economy of expression were mixed with large stretches of laughter. The readable sections contained the code for making cellular proteins; the other regions, which represented about 90% of the entire genome, were dismissed as “junk DNA”, with no discernible purpose.

Research has taught researchers otherwise. Far from being a 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 researchers, this has raised its own questions: if mutations in coding regions cause cells to make deficient proteins, what do mutations in non-coding regions do? How does a mutation in the interior of the genome – in areas without genes – contribute to cancer?

Given that non-coding regions are involved in gene regulation, researchers have, of course, hypothesized that mutations in these zones play havoc with gene activity in a way that promotes cancer. Study after study, however, has found that this is generally not the case, leaving the biological effect of non-coding mutations somewhat of a mystery.

Thinking locally

In a new issue of the newspaper Natural genetics, gave Dana-Farber investigators an answer. They did so through the scientific equivalent of thinking locally – limiting the scope of their research to the specific DNA where 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 density of the DNA in these sites. This in turn affects how open these sites are to bind to other parts of DNA or certain proteins, all of which can affect the activity of genes involved in cancer.

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

“Studies have identified a huge number of mutations in the genome that are potentially involved in cancer,” said Alexander Gusev, PhD, at Dana-Farber, Eli and Edythe L. Broad Institute and Brigham and Women’s Hospital, who co-authored the dissertation with Dana-Farber. Farbers Dennis Grishin, PhD. “The challenge has been to understand the biology through which these variations increase the risk of cancer. Our study has revealed an important part of that biology.”

Does mutation change expression?

To identify hereditary, or germ cells, mutations that increase a person’s risk of developing cancer, investigators conduct so-called comprehensive association studies or GWAS. In these, 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 people with cancer than in those without the disease.

Such tests have yielded thousands of such mutations, but only a small proportion of them are found in coding parts of the genome that are relatively easy to link to cancer. Breast cancer is an example. “More than 300 mutations have been identified that are associated with an increased risk of the disease,” says Gusev. “Less than 10% of them are actually in genes. The rest are in ‘desert’ regions, and it has not been clear how they affect the risk of disease.”

To try to make that connection, researchers are collecting two sets of data: one, GWAS data showing mutations in a specific type of cancer; and two, data on another genomic trait of that 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 if the mutations correspond to an increase or decrease in the activity of these genes. If such a relationship exists, it would help explain how non-coding mutations can lead to cancer.

Despite a massive investment in this type of research, however, co-location studies have shown very few such correspondences. “The large number of mutations identified by GWAS has been shown to have no co-localizing gene at all,” says Gusev. “For the most part, non-coding mutations associated with cancer risk do not overlap with changes in gene expression. [activity] documented in public data sets. “

Looking closer to home

With the path that seemed increasingly uninformative, Gusev and Grishin tried another, more basic approach. Instead of starting with the assumption that non-coding mutations can affect gene expression, they asked how they change their home environment – whether they affect the winding of DNA in their immediate vicinity.

“We assumed that if you looked at the effect of these mutations on local epigenetics – specifically, whether they caused nearby DNA to be more densely wound or loosened – we could detect changes that would not be obvious in expression-based studies,” says Gusev.

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

It’s as if previous studies were trying to understand how a brush fire in California could affect the weather in Colorado, while Gusev and Grishin wanted to see its effect on the slope where it started.

To do so, they performed another type of overlay 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 crossed each other.

The results were in sharp contrast to those from co-location studies. We found that while most non-coding mutations do not have an effect on gene expression, most of them do has an impact on local epigenetic regulation, “says Gusev.” We now have a basic biological explanation of how the vast majority of cancer risk mutations are potentially linked to cancer, whereas previously no such mechanism was known. “

With this approach, the researchers created a database of mutations that can now be linked to cancer risk through a known biological mechanism. The database can serve as a starting point for research on drugs that, by targeting that mechanism, can lower an individual’s 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 that factor, potentially reducing the likelihood that people born with that mutation will develop cancer, Gusev says.

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