Two major studies published in Nature have uncovered a new level of control of cancer gene activity within tumors, termed cancer's "dark matter."
The revelation shows that epigenetics, cells controlling gene activity, play a crucial role in the development of cancer. Cancers are usually tested for DNA mutations alone, which can miss this level of control, thereby failing to predict how cancers may behave and respond to treatment.
Professor Trevor Graham, Director of the Centre for Evolution and Cancer at the Institute of Cancer Research (ICR), said in a statement: "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."
The research was led by scientists at The Institute of Cancer Research, London, Human Technopole in Milan, and the Queen Mary University of London.
With these studies, scientists were able to track the influence of epigenetic control on the growth and evolution of bowel cancers. They also noted that epigenetic changes are heavily involved in cancer's evolution.
"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," said Graham.
The papers unearthed the key discovery
According to the statement by ICR, the papers represent a "fundamental advance" in the world's understanding of cancer. The studies explain why DNA tests can be unreliable when it comes to cancer's response to treatment. It can now help doctors to customize treatments for patients in a better manner.
"We have for the first time been able to map epigenetic changes alongside the accumulation of DNA mutations as a colorectal tumor 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," said Professor Andrea Sottoriva, Head of the Computational Biology Research Centre at Human Technopole in Milan, who co-led the research.
Professor Kristian Helin, Chief Executive of the ICR, London, and a world leader in the study of epigenetics, said that the research opens exciting future opportunities to examine cancer employing "both genetic and epigenetic tests, and eventually to treat cancer with epigenetic-directed drugs."
Abstract (The co-evolution of the genome and epigenome in colorectal cancer)
Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4,5,6,7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.
Originally published in Interesting Engineering
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