The ‘dark matter’ behind cancer

DNA unwinding from histones

DDW Editor Reece Armstrong looks into recent research which may explain why cancers can become more aggressive.

Researchers in London and Milan may have discovered why cancers can become more aggressive without relying only on DNA mutations.

A lot of research to do with cancer has focused on the way cancers can occur and evolve due to mutations in DNA. However, this recent research indicates that ‘epigenetics’ – or the level of gene control within tumours – is crucial to how a cancer develops and progresses.

The research, published in Nature1,2 comprises of two studies looking at the role of epigenetics in bowel cancer and why cancer cells within the same tumour can be so different to one another.

The studies were led by teams at The Institute of Cancer Research, London, Human Technopole in Milan and Queen Mary University of London. 

Epigenetics sees the three-dimensional structure of DNA undergo chemical changes without altering the DNA code itself. It can also control access to genes and has been recognised as playing an important role in the development of cancer. 

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.

The researchers have characterised an extra level of control of cancer gene activity within tumours, describing the development as cancer’s ‘dark matter’.

In bowel cancer, the scientists tracked the influence of epigenetic control for how tumours grow, develop and evolve over time. They found signs that epigenetic changes are involved in cancer’s ability to evolve and become more aggressive.

The team collected 1,373 samples from 30 bowel cancers and found that epigenetic changes are common in cells which have become cancerous and occur around genes already known to drive cancer. They also found that epigenetic changes can be inherited by cells within each cell division, contributing to a cancer’s evolution. Moreso, the team found that epigenetic changes influence how cancer cells accumulate DNA mutations and that they had survival advantages which helped them to grow more than other cells.  

In the second study, the scientists examined the DNA sequence in diverse samples taken from different parts of the same tumour. Understanding why tumours can have cancers cells remarkably different to each other could help scientists’ understand why some cells develop survival advantages and become resistant to cancer treatments.

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

Whilst the research is observational in nature, the studies help advance our understanding into how cancer develops in the body. The researchers state that DNA mutations help ‘set the scene’ for a cancer’s development and evolution, but that subsequent behaviour of cancer cells can be determined by factors such as epigenetics. 

This could explain why DNA tests don’t always predict how cancers will respond to certain treatments. It could also help lead to tailored treatments and more accurate cancer diagnostic tests. 

Speaking about the research, Professor Trevor Graham, Director of the Centre for Evolution and Cancer at The Institute of Cancer Research, London, says: “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 Kristian Helin, Chief Executive of The Institute of Cancer Research, London, says the 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,” Professor Helin adds.

DDW Volume 24 – Issue 1, Winter 2022/2023

References

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

Image shows: DNA unwinding from histones. The 3D structure of DNA can influence which genes can be turned on and off. Credit: Phospho Biomedical Animation.

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