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"Dark Matter" That Shapes Cancer Behavior Unveiled in Landmark Studies

Graphical representation of DNA unwinding from histones.
DNA unwinding from histones. Credit: Phospho Biomedical Animation

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Cancers can evolve to become more aggressive without relying only on DNA mutations, two major studies published simultaneously in Nature reveal.


The research characterizes a whole extra level of control of cancer gene activity within tumours, which the researchers describe as cancer’s "dark matter".


The two landmark studies showed how a level of gene control called ‘epigenetics’ plays a central role in the development and progression of bowel cancer. Testing cancers for DNA mutations alone misses this level of control – and so can fail to predict how cancers may behave and respond to treatment.


The research, published today in Nature, 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.

More accurately predict cancer's behaviour

The research could change the way we think about cancer and its treatment – and lead to new forms of tests that predict cancer’s behaviour more accurately.


Epigenetics involves chemical changes to the three-dimensional structure of DNA which don’t alter the DNA code itself but can control access to genes. It has increasingly been recognised as playing an important role in the development of cancer.


Now for the first time, scientists have been able to track the influence of epigenetic control on how bowel cancers grow, develop and evolve over time, separately from the influence of mutations to the DNA code, which they mapped simultaneously.


The researchers observed important epigenetic changes in every cancer they examined and found signs that epigenetic changes are involved in cancer’s ability to evolve and become more aggressive.


In the first paper, the researchers collected 1,373 samples from 30 bowel cancers and looked at epigenetic changes as cancers evolved. They showed that epigenetic changes:

  • are highly common in cells which have become cancerous and occur around genes already known to drive cancer
  • are heritable, meaning they can be inherited by cells with each cell division, and that they contribute to cancer evolution
  • influence how cancer cells accumulate DNA mutations
  • were present in cancer cells that had survival advantages which helped them to grow more than other cells.

Survival advantages

The second Nature paper aimed to understand why cancer cells within the same tumour can be so different to one another – a characteristic that helps some cells develop survival advantages and become resistant to cancer treatments.


The researchers wanted to understand whether the diversity of cell types within a tumour 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 tumour.


They found:

  • less than 2 per cent of changes in the DNA code in independent areas of a tumour were associated with changes in gene activity
  • variation in cancer cell characteristics throughout tumours is often governed by factors other than DNA mutations.

The researchers point out 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 to cancer behaviour.

Fundamental advance in our understanding of cancer

Collectively, the papers represent a fundamental advance in our understanding of cancer. The researchers stress that DNA mutations are fundamental in "setting the scene" for a cancer’s development and evolution – but that much of the subsequent behaviour of cancer cells is determined by other factors, such as epigenetics.


That could help explain why DNA tests don’t always predict how cancers will respond to treatment and help doctors to tailor treatments for patients more effectively. It could also explain why some environmental exposures can cause cancer without leading to mutations in the DNA code.


Professor Trevor Graham, Director of the Centre for Evolution and Cancer at the ICR, 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.”


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 tumour 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 ICR, London, and a world leader in the study of epigenetics, said:


“This 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 behaviour. It opens exciting future opportunities to assess cancer using both genetic and epigenetic tests, and eventually to treat cancer with epigenetic-directed drugs."


References:

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


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