‘Dark matter’ creates a whole new level of cancer gene activity in tumors, researchers say

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A whole new level of control of cancer gene activity within tumors, has been described by researchers as ‘dark matter’.

It was recently discovered and published in two major studies at the same time in Nature that cancers can evolve to become more aggressive without relying on DNA mutations.

Testing cancers for just the DNA mutations can skip this level of control and therefore fail to predict how cancers may behave and respond to treatment, the researchers say.

Both studies revealed how a level of gene control called ‘epigenetics’ pays a central role in the progression and development of bowel cancer.

The research was led by scientists at The Institute of Cancer Research, London, Human Technopole in Milan and Queen Mary University of London. It was funded by Wellcome, the Medical Research Council (MRC) and Cancer Research UK.

Dark matter could accurately predict cancer’s behavior

The researchers say their findings could change the way cancer is thought about and the way it is treated – and lead to new forms of tests that predict cancer’s behavior more accurately.

The chemical changes that occur to the three-dimensional structure of DNA through epigenetics, do not change the DNA code but it can control access to genes. The researchers said it has increasingly been recognized as playing a major role in the development of cancer.

The influence of epigenetic control on how bowel cancers grow and develop over time was tracked for the first time thanks to the scientists’ work. They managed to track this separately from the influence of mutations to the DNA code, which were mapped at the same time.

For every cancer they examined, the researchers noted important epigenetic changes that they noted were involved in the disease’s ability to evolve and become more aggressive.

‘Something we liken to cancer’s dark matter’

Professor Trevor Graham, director of the center for evolution and cancer at the Institute of Cancer Research, said: “We’ve unveiled an extra level of control for how cancers behave – something we liken to cancer’s ‘dark matter’. For years our understanding of cancer has focused on genetic mutations which permanently change the DNA code. But our research has shown that the way the DNA folds up can change which genes are read without altering the DNA code and this can be very important in determining how cancers behave.

“I hope our work will change the way we think about cancer and its treatment – and should ultimately affect the way patients are treated. Genetic testing for cancer mutations only gives us part of the picture about a person’s cancer – and is blind to ‘epigenetic’ changes to how genes are read. By testing for both genetic and epigenetic changes, we could, potentially, much more accurately predict which treatments will work best for a particular person’s cancer.”

The researchers collected 1,373 samples from 30 bowel cancers and looked at the epigenetic changes as the cancers evolved which was recorded in the first paper.

Cancer evolution

They noted that epigenetic changes are highly common in cells which have become cancerous and occur around genes already known to drive cancer.

They found they are heritable, meaning they can be inherited by cells with each cell division, and that they contribute to cancer evolution and they influence how cancer cells accumulate DNA mutations.

The changes were also present in cancer cells that had survival advantages which helped them to grown more than other cells.

Survival advantages

In the second paper, the researchers were trying to understand why cancer cells within the same tumor can be so different to one another, a characteristic the researchers said, helps some cells develop survival advantages becoming resistant to cancer treatments.

The researchers, wanted to understand whether the diversity of cell types within a tumor was governed by variation in the DNA code or something else. DNA sequences in diverse samples

The researchers wanted to understand whether the diversity of cell types within a tumor is governed by variation in the DNA code, or something else. They looked at the DNA sequence in diverse samples taken from different parts of the same tumor.

They found that less than 2% of changes in the DNA code in independent areas of a tumor were associated with changes in gene activity and  that variation in cancer cell characteristics throughout tumors is often governed by factors other than DNA mutations.

Specific epigenetics

The researchers point out that more work needs to be done to determine cause and effect between specific epigenetic changes and modifications to cancer behavior and their findings are observational in nature.

Together, the researchers say that the papers represent a fundamental advance in understanding cancer. They stress DNA mutations are essential for ‘setting the scene’ for a cancer’s development and the way it evolves but importantly note that much of the subsequent behavior of cancer cells is determined by other factors such as epigenetics.

The researchers believe this could help explain why DNA tests don’t always predict how cancers are going to respond to treatment in order to help doctors tailor treatments for patients more effectively. They say it could also give reason as to why some environmental exposures can cause cancer without leading to mutations in the DNA code.

DNA mutations

Professor Andrea Sottoriva, head of the computational biology research centre at human technopole in Milan, who co-led the research, said: “When we study how cancers evolve over time, we tend to look at DNA mutations, but it’s clear that epigenetic changes also enable cancer to adapt and develop a survival advantage over other cells.

“We have for the first time been able to map epigenetic changes alongside the accumulation of DNA mutations as a colorectal tumor evolves. This provides exciting opportunities to create new treatments for cancer that don’t target the effects of DNA mutations, but instead the epigenetic changes which determine how genes are read.”

‘Open’s up exciting future opportunities’

Professor Kristian Helin, chief executive of the Institute of Cancer Research, and a world leader in the study of epigenetics, said: “This (dark matter) discovery represents an exciting advance in our understanding of cancer biology.  Cancer’s ability to rapidly change and evolve is a key reason why it is so hard to treat. Exactly how cancer cells do this, and the factors that control how it can adapt to evade treatment, is not well understood.

“This important work demonstrates the potential role of epigenetic regulation in the development of cancer and the complexity of its behavior. It opens exciting future opportunities to assess cancer using both genetic and epigenetic tests, and eventually to treat cancer with epigenetic-directed drugs.”

The Institution of Cancer Research is is one of the world’s most influential cancer research institutes and can now add ‘dark matter’ to its list of research achievements while it continues researching how to treat the differences between cancers.

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