Cancers can evolve to become more aggressive without relying solely on DNA mutations, reveal two important studies published simultaneously in Nature.
The research characterizes a whole additional level of control of cancer gene activity within tumors, which researchers describe as the “dark matter” of cancer.
The two landmark studies showed how a level of genetic control called “epigenetics” plays a central role in the development and progression of bowel cancer. Testing cancers for DNA mutations alone does not have this level of control and therefore may not predict how cancers may behave and respond to treatment.
The research, published today in Nature, was led by scientists from the Institute of Cancer Research in 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.
It more accurately predicts cancer behavior
The research could change the way we think about cancer and its treatment, and lead to new forms of testing that predict cancer behavior more accurately.
Epigenetics involves chemical changes to 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 that it plays 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 in the DNA, which they mapped simultaneously.
The researchers observed significant epigenetic changes in all the cancers they examined and found signs that epigenetic changes are involved in cancer’s ability to evolve and become more aggressive.
In the first paper, researchers collected 1,373 samples from 30 bowel cancers and analyzed epigenetic changes as the cancers evolved. They showed that epigenetic changes:
- they are very common in cells that have become cancerous and occur around genes that are already known to cause cancer
- they are heritable, that is, they can be inherited by cells with each cell division and contribute to the development of cancer.
- influence how cancer cells accumulate DNA mutations
- they were present in cancer cells that had survival advantages that helped them grow more than other cells.
Survival advantages
The second Nature paper sought to understand why cancer cells in the same tumor can be so different from one another, a characteristic that helps some cells develop survival advantages and be resistant to cancer treatments.
The researchers wanted to understand whether the diversity of cell types within a tumor is governed by variation in the DNA code or by something else. They looked at the DNA sequence in several samples taken from different parts of the same tumor.
They found:
- less than 2% of changes in the DNA code in areas independent of a tumor were associated with changes in gene activity.
- variation in cancer cell characteristics throughout tumors is often governed by factors other than DNA mutations.
The researchers note that their findings are observational in nature, and more work is needed to determine cause and effect between specific epigenetic changes and changes in cancer behavior.
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 central to “setting the stage” for the development and evolution of a cancer, but that much of the subsequent behavior of cancer cells is determined by other factors, such as epigenetics.
This could help explain why DNA tests don’t always predict how cancers will respond to treatment and help doctors tailor treatments to patients more effectively. It could also explain why some environmental exposures can cause cancer without causing mutations in the DNA code.
Professor Trevor Graham, Director of the ICR’s Center for Evolution and Cancer, said:
“We have unveiled an additional level of control over how cancers behave, something we liken to the ‘dark matter’ of cancer. For years, our understanding of cancer has focused on genetic mutations that permanently change 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 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 picture of a person’s cancer and are blind to “epigenetic” changes in the way genes are read. By testing for genetic and epigenetic changes, we could potentially much more accurately predict which treatments will work best for the cancer of a particular person.”
Professor Andrea Sottoriva, head of the Computational Biology Research Center 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 allow cancer to adapt and develop a survival advantage over other cells.
“For the first time we have been able to map epigenetic changes along with the accumulation of DNA mutations as a colorectal tumor evolves. This offers exciting opportunities to create new cancer treatments that do not target the effects of DNA mutations, but to epigenetic changes that determine how genes are read.”
“Unlock exciting future opportunities”
Professor Kristian Helin, Chief Executive of 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 change and evolve rapidly is a key reason why it is so difficult to treat. Exactly how cells do this is not well understood. Cancer cells and the factors that control how they can adapt to evade treatment.
“This important work demonstrates the potential role of epigenetic regulation in cancer development and the complexity of its behavior. It opens up exciting future opportunities to assess cancer using genetic and epigenetic testing and ultimately to treat cancer with targeted drugs ‘epigenetics’.
References:
- Heide T, Househam J, Cresswell GD, et al. The coevolution of the genome and the epigenome in colorectal cancer. Nature. 2022: 1-11. two: 10.1038/s41586-022-05202-1
- Househam J, Heide T, Cresswell GD, et al. Phenotypic plasticity and genetic control in the evolution of colorectal cancer. Nature. 2022: 1-10. doi: 10.1038/s41586-022-05311-x
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