In 1976, Peter Nowell first formally described cancer as an evolutionary process. This was the beginning of the notion that tumours are in fact adapting in response to selective pressures, whether this be the body’s immune system or anticancer therapies. Until recently, it was thought that genetic changes were sufficient to cause cancer. However, it is now becoming clear that both changes in the genome and epigenome play a significant role in the evolution of cancer.
In an issue of Science, authors Professor Toshikazu Ushijima, Professor Patrick Tan and Professor Susan Clark reviewed how analysing DNA in its full complexity can provide insights into cancer. Here we discuss some of the main take home messages.
What is the cancer epigenome?
Epigenetic processes play a central role in cancer causation, progression and treatment. The word ‘epigenetic’ literally means ‘in addition to changes in genetic sequence’. In reality, epigenetics is the study of any process that alters gene activity without changing the DNA sequence. The main types of epigenetic processes include methylation, acetylation, phosphorylation, ubiquitylation and sumolyation.
Global changes in the epigenetic landscape are a hallmark of cancer. The cancer epigenome is mainly characterised by alterations in DNA methylation and histone modification patterns, in addition to altered expression profiles of chromatin-modifying enzymes. For example, there is now evidence to suggest that changes to DNA methylation that occur during ageing may predispose cells to cancer-causing genetic changes. Moreover, scientists have observed DNA methylation changes in cells caused by cigarette smoking before genetic changes and lung cancer could be detected.
As a result, in order to gain new insights into what drives carcinogenesis, both genomic and epigenomic changes need to be mapped. Understanding how the epigenome evolves during the cancer life cycle will be crucial for improving cancer risk assessments and patient outcomes. The epigenome has been linked to cancer transitioning from a primary tumour to metastasis and is now known to be involved in the development of resistance to treatment. Improving our knowledge about these changes, alongside utilising the reversible nature of epigenetic aberrations, could lead to new precision cancer therapies to treat advanced disease.
How to explore cancer evolution
Gaining new biological insights into cancer evolution will be crucial for accelerating discoveries in the field and improving patient outcomes. Throughout the last two decades, technologies have been developed that enable scientists to explore the complexity of the genome and epigenome. Today, advanced imaging and single-cell technologies are helping to create 3D maps of various cells that inhabit tumour microenvironments at unprecedented resolution.
But the wealth of diverse sequencing and imaging datasets also pose huge challenges for scientists in terms of data integration. The wealth of information generated by these studies has already, and will continue to, exceed the capability of humans alone. Therefore, computational forces, such as artificial intelligence, will help to solve the mathematical problems that arise from big data and enable scientists to gain valuable insights into cancer evolution.
Additionally, researchers will need to develop methods for integrating complex datasets being generated by different analysis techniques and laboratory methods. The creation and implementation of globally standardised approaches will be crucial for understanding how to combine information about how the relationships between different layers of DNA can lead to cells becoming cancerous. Then, translating these genomic and epigenomic findings into feasible clinical applications poses another challenge. Nevertheless, it is hoped that future studies will shed light on the detrimental epigenetic signatures involved in cancer evolution as well as the precise steps that lead to tumour formation. This in turn will improve cancer screening and even help to remove carcinogenic agents from our environment altogether.
Image credit: Scientific American