‘Dark matter’ shaping cancer behavior has been revealed in landmark studies

Cancer can evolve to become more aggressive without relying solely on DNA mutations, two large studies published at the same time in Nature discover.

The research characterizes a whole additional level of control over the activity of cancer genes within tumors, which the researchers refer to as the “dark matter” of cancer.

The two landmark studies showed how a level of gene control called ‘epigenetics’ plays a central role in the development and progression of colorectal cancer. Testing cancers for DNA mutations alone falls short of this level of control — and therefore may not predict how cancers will behave and respond to treatment.

The research, published today in Nature, 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.

Predict cancer behavior more accurately

The research could change the way we think about cancer and its treatment – and lead to new forms of testing that more accurately predict how cancer will behave.

Epigenetics involves chemical changes in the three-dimensional structure of DNA that do not alter the DNA code itself, but can control access to genes. It has been increasingly recognized to play an important role in the development of cancer.

Now, for the first time, scientists have been able to trace the influence of epigenetic control on the growth, development and temporal development of colorectal cancer independently of the influence of mutations on the DNA code, which they simultaneously mapped.

The researchers observed important epigenetic changes in every cancer they studied and found evidence that epigenetic changes are involved in the ability of cancers to develop and become more aggressive.

In the first publication, the researchers collected 1,373 samples from 30 types of colorectal cancer and examined epigenetic changes during cancer development. They showed that epigenetic changes:

• are very common in cells that have become cancerous and occur near genes already known to cause cancer
• are heritable, meaning that they can be inherited by cells every time cells divide, and that they contribute to the development of cancer
• affect how cancer cells accumulate DNA mutations
• were present in cancer cells that had survival advantages that helped them grow more than other cells.

survival benefits

The second Nature The goal of this work was to understand why cancer cells can be so different within the same tumor—a trait that 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. They examined the DNA sequence in different samples taken from different parts of the same tumor.

They found:

• less than 2 percent of changes in the DNA code in independent regions of a tumor were associated with changes in gene activity
• Variations in the properties of cancer cells in tumors are often determined by factors other than DNA mutations.

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

Fundamental advances in our understanding of cancer

Taken together, the papers represent a fundamental advance in our understanding of cancer. The researchers emphasize that DNA mutations are fundamental to “staging” a cancer’s development and evolution – but that much of the subsequent behavior of cancer cells determined by other factors such as epigenetics.

That could explain why DNA testing doesn’t always predict how cancer will respond to treatment, and help doctors more effectively match treatments to patients. It could also explain why some environmental exposures can cause cancer without causing mutations in the DNA code.

Professor Trevor Graham, Director of the Center for Evolution and Cancer at ICR said:

“We have discovered an additional layer of control over cancer behavior – something we liken to cancer’s ‘dark matter’. 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.”

Professor Andrea Sottoriva, head of the Computational Biology Research Center at the Human Technopole in Milan, who co-led the research, said:

“When we study how cancer evolves over time, we typically look at DNA mutations, but it’s clear that epigenetic changes also allow 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, Chief Executive of the ICR, London, and a world leader in epigenetics research, said:

“This discovery represents an exciting advance in our understanding of cancer biology. Cancer’s ability to rapidly change and progress is a key 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.”

References:

1. Heide T, Househam J, Cresswell GD, et al. The co-evolution of genome and epigenome in colorectal cancer. Nature. 2022:1-11. doi: 10.1038/s41586-022-05202-1
2. Househam J, Heide T, Creswell GD, et al. Phenotypic plasticity and genetic control in colon cancer evolution. Nature. 2022:1-10. doi: 10.1038/s41586-022-05311-x

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