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

A whole new level of control over the activity of cancer genes within tumors has been described by researchers as “dark matter”.

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

Testing cancers just for DNA mutations may skip this level of control and therefore not predict how cancers will behave and respond to treatment, the researchers say.

Both studies showed how a level of gene control termed “epigenetics” plays a central role in the progression and development of colorectal cancer.

The research was led by scientists from the Institute of Cancer Research, London, the 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 behavior

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

The chemical changes that occur to the three-dimensional structure of DNA through epigenetics do not change the DNA code, but they can control access to genes. According to the researchers, it is increasingly recognized that it plays an important role in the development of cancer.

The impact of epigenetic control on the growth and development of colorectal cancer over time has been tracked for the first time thanks to the scientists’ work. They managed to track this separately from the impact of mutations on the DNA code, which were being mapped at the same time.

In each cancer studied, the researchers identified key epigenetic changes that they found were implicated in the disease’s ability to develop and become more aggressive.

“Something we liken to the dark matter of cancer”

Professor Trevor Graham, director of the Center for Evolution and Cancer at the Institute for Cancer Research, said: “We have developed an additional layer of control over the behavior of cancer – something that we liken to the ‘dark matter’ of cancer. For years, our understanding of cancer has focused on genetic mutations that permanently alter the DNA code. But our research has shown that the way DNA folds can change which genes are read without altering the DNA code, and this can be very important in determining how cancers behave.

“I hope that our work will change the way we think about cancer and its treatment – and ultimately impact 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 in how genes are read. By testing for both genetic and epigenetic changes, we could potentially be much more accurate in predicting which treatments would work best for a given person’s cancer.”

The researchers collected 1,373 samples from 30 types of colorectal cancer and examined the epigenetic changes during the development of the cancer types recorded in the first publication.

cancer development

They found that epigenetic changes are very common in cells that have become cancerous and occur around genes already known to cause cancer.

They found that they are heritable, meaning they can be inherited by cells every time cells divide, and that they contribute to cancer development and affect how cancer cells accumulate DNA mutations.

The changes were also present in cancer cells, which had survival advantages that helped them grow stronger than other cells.

survival benefits

In the second publication, the researchers attempted to understand why cancer cells can be so different within the same tumor, a trait the researchers say helps some cells develop survival advantages and become resistant to cancer treatments.

The researchers wanted to understand whether the variety of cell types within a tumor is determined by variations in the DNA code or something else. DNA sequences in various samples

The researchers wanted to understand whether the variety of cell types within a tumor is determined by variations in the DNA code or something else. They examined the DNA sequence in different samples taken from different parts of the same tumor.

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

Specific Epigenetics

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

Together, the researchers say the papers represent a fundamental advance in understanding cancer. They emphasize that DNA mutations are essential to “set the stage” for a cancer’s development and the way it develops, but also note that much of the later behavior of cancer cells is influenced by other factors such as determined by epigenetics.

The researchers believe this could explain why DNA testing doesn’t always predict how cancer will respond to treatment, to help doctors more effectively match treatments to patients. They say it could also provide a reason why some environmental exposures can cause cancer without causing mutations in the DNA code.

DNA mutations

Professor Andrea Sottoriva, head of the Research Center for Computational Biology at the Human Technopole in Milan, who co-led the research, said: “When we study how cancer develops over time, we usually look at DNA mutations, but it is clear that changing epigenetic changes also allows cancer to adapt and develop a survival advantage over other cells.

“For the first time, we were able to map epigenetic changes together with the accumulation of DNA mutations during the development of a colorectal tumor. This offers exciting opportunities to develop new treatments for cancer that do not target the effects of DNA mutations, but rather the epigenetic changes that determine how genes are read.”

‘Opens up exciting future opportunities’

Professor Kristian Helin, Executive Director of the Institute for Cancer Research and a world leader in the study of epigenetics, said: “This discovery (dark matter) represents an exciting advance in our understanding of cancer biology. Cancer’s ability to rapidly change and evolve, is a major reason it is so difficult to treat. Exactly how cancer cells do this and what factors control how they 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 up exciting possibilities for the future of assessing cancer using both genetic and epigenetic testing and ultimately treating cancer with epigenetically targeted drugs.”

The Institution of Cancer Research is one of the most influential cancer research institutes in the world and can now add “dark matter” to its list of research achievements as it continues to explore how to treat the differences between cancer types.