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Searching in the dark: The role of epigenetics in cancer development

New research, led by scientists at The Institute of Cancer Research, the Human Technopole in Milan, and Queen Mary University of London, has uncovered the role of epigenetics in colorectal cancer (CRC) development. The findings, published across two papers in Nature, highlight the importance of including epigenetics testing in genomic medicine and point to potential future avenues for improving treatment efficacy.

Discovering dark matter

In contrast to the DNA mutations found in the cancer genome, epigenetics has no effect on our genetic code. Instead, it alters the 3D structure of DNA and can control gene accessibility. Traditionally, most research has focused on changes in our DNA code and how these changes (mutations) drive the growth of cancers. This has led to genetic testing that often overlooks an entire other layer of control (the epigenome) and makes it difficult to predict how cancers will respond to treatment.

Researchers are now recognising the impact of our epigenome on the development and evolution of cancers, but there is still a lack of research into how these structural changes influence things like tumour heterogeneity. In a bid to fight this lack of research, Trevor Graham (Director, Centre for Evolution and Cancer, The Institute of Cancer Research in London) and his colleagues have recently published two separate papers exploring the link between epigenetics and cancer.

“We’ve unveiled an extra level of control for how cancers behave – something we liken to cancer’s ‘dark matter’,” said Graham.

The colorectal connection

The first of these papers looked at the co-evolution of the genome and epigenome of CRC tumours using spatial and multi-omic profiling of individual colon glands. In total, 1,373 samples were collected from 30 bowel cancers and the team created 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. Using this approach, they were able to track how CRC tumours develop over time separately from mutations in the DNA code, which they mapped simultaneously.

Figure 1: Spatial single-gland multi-omics. A-d, The process followed: fresh colectomy specimens from 30 patients with stage I–III CRC were used to collect tissue from 30 cancers and 8 adenomas. Single glands and small bulks (minibulks) were isolated from normal and neoplastic samples. Cell lysis followed by nuclei pelleting on each sample. d, Cytosolic fractions were used for RNA-seq whereas nuclei were used for WGS and ATAC-seq. e, Identification of separate regions of the specimen. f, From each fragment, individual glands were collected as well as minibulks. g, Multi-omics analysis was performed using WGS, ATAC-seq and RNA-seq on the same sample. h, Each assay included representative samples from normal, adenoma and cancer regions. Graphics in b–d were created with

They found that changes in the epigenome were common in cancerous cells and occur around genes known to be drivers of cancer. They also found that these changes were highly heritable (they are inherited with each cell division) meaning they influence how cells accumulate DNA mutations.

Tumour heterogeneity

The second paper looked at why cells from the same tumour can be so different – a strategy that helps cancers evolve and become resistant to certain treatments.

The team studied diverse samples taken from different parts of the same tumour using spatially resolved paired whole-genome and transcriptome sequencing. They found that less than 2% of the changes in DNA code were associated with changes in gene activity – in other words, most genetic intratumor variation has no bearing on phenotypes – and that transcriptional plasticity is widespread in CRC.

“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,” said Graham.

Treating tumours

Overall, the two papers have highlighted the role of other influences, outside of DNA mutations, on the development and behaviour of cancers. The findings could also explain how environmental exposures can cause cancer without changing our genetic code.

However, some of these findings are purely observational and more work is needed to show a definitive link between the epigenome and its role in cancer progression. “We have for the first time been able to map epigenetic changes alongside the accumulation of DNA mutations as a colorectal tumour evolves,” said Andrea Sottoriva, Head of the Computational Biology Research Centre at Human Technopole in Milan, who co-led the research. “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.”

Graham shares this sentiment: “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.”