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For years, researchers thought of cancer as a genetic disease, caused by mutations or alterations to the order of the genetic code. While this isn’t incorrect, it’s becoming clear that this is only part of the story.
“The last few years have increased the awareness that it’s not just genetic mutations that lead to cancer,” says Dr Cynthia Hawkins, a pathologist and researcher at Toronto’s Hospital for Sick Children. “There are a lot of things in cells that can lead to cancer.”
Changes to genes that do not alter the underlying DNA sequence can have a profound effect on how genes are read and interpreted to perform their activities, which in turn can lead to a number of diseases, including cancer.
DNA is packaged in a specific way
Most cells in our bodies carry a complete set of DNA, containing all of the genes that carry instructions for our growth, development and features. If stretched out, the DNA in each cell would measure about 2 metres long, yet it fits inside a compartment in the cell called the nucleus, which is about 1/10 as wide as an average human hair.
To fit in the nucleus, DNA is tightly wound and packaged around proteins called histones. These DNA-histone structures are called chromatin and condense further to form chromosomes.
When they are tightly coiled, most of the genes in the DNA are not able to be turned on. When a specific gene needs to be switched on, the part of the chromosome where it resides unwinds and opens up so that the gene can be accessed, while genes that aren’t needed remain tucked away. This process is highly regulated to ensure that the right genes are read at the right time, but this is precisely where things can go wrong. A gene that should be read may be silenced, or a gene that should be silenced is read. The biological processes behind these errors are called epigenetics.
Epigenetics plays a role in cancer development
Epigenetics refers to changes to the genetic material or its organization that are not changes to the order of the letters in DNA, known as the DNA sequence. Instead, epigenetic processes affect how genes interact with the environment around them and how they are read and interpreted. Small chemical structures become attached to chromatin and affect which genes are “expressed” or turned on, ultimately affecting cell processes like growth, development and DNA repair.
Epigenetic processes play important roles in ensuring that the right genes are accessed and read at the right time, and they are critical for proper cell growth and development. However, if an epigenetic change occurs when or where it shouldn’t, problems can arise.
Epigenetic changes can accumulate over time and are caused by a number of different factors including environmental or lifestyle-based exposures such as smoking, an unhealthy diet or exposure to toxins. Age and chronic inflammation are also known contributors.
Left unchecked, these epigenetic changes can lead to cancer and affect how the disease spreads and responds to drugs. At the same time, these changes are also reversible – which makes them ideal targets for cancer treatment.
Most common types of epigenetic changes
There are several different kinds of epigenetic changes, all of which can influence which genes are switched on.
DNA methylation silences critical genes
Researchers have long known that DNA methylation plays a role in cancer. In this process, a chemical structure called a methyl group attaches to various locations on a DNA strand. These chemicals get in the way of the machinery that reads the gene, effectively silencing it.
Not every gene needs to be expressed in every cell all the time. Methylation is actually an important part of development, but researchers have found that cancer cells and healthy cells have very different methylation patterns.
Cancer cells often have more methylation than healthy cells, which silences genes that normally block tumour growth. Less commonly, cancer cells may have lower DNA methylation than healthy cells, which can activate a gene that promotes cancer growth.
Histone changes affect DNA structure
Histone proteins help give structure to DNA. A strand of DNA winds around histones and forms chromatin that condenses to fit into the nucleus of a cell. This packaging needs to happen in a particular way in order for cells to access the proper genes needed to run the cell.
If a chemical group attaches to the histone at an incorrect location, the chromatin structure can change in such a way that a gene that needs to be turned on may be inaccessible while a gene that should be tucked away may be activated.
“The location of the histone modification really matters,” says Dr Bernhard Lehnertz, a researcher at the University of Montreal. “The precise location will determine the structure of the chromatin and whether genes are activated or suppressed.”
Non-coding RNA interferes with interpreting the genetic code
The genetic code provides the instructions needed for the body to make proteins, but a molecule called RNA is needed to act as the interpreter of the genetic code and make the proteins. RNA is a molecule made of genetic material, similar to DNA, and it helps to put the genetic code into action.
Non-coding RNA, which are usually very small pieces of RNA, can interfere with the genetic code. It can attach to an RNA molecule, or sometimes DNA, and stop a particular gene from being expressed.
In a healthy cell, non-coding RNAs, like DNA methylation and histone changes, are highly regulated and play an important role in a variety of cell processes, including cell growth and death. But if they attach at the wrong place or time, a variety of different issues can result, including cancer development and spread.
Using epigenetic changes for cancer diagnosis and treatment
For cancer to develop, a healthy cell undergoes several biological changes to start growing uncontrollably and avoid the body’s defenses. Both genetic mutations and epigenetic processes may be involved in this transformation.
While researchers have studied genetic mutations in cancer for many years, the role of epigenetics in cancer development is not as well understood, though it is improving thanks to technology. “The tools to study epigenetics are getting much better,” says Dr Hawkins. “Even in the last five years, more tools to study epigenetic changes across the whole set of genes are available, it is more accessible and more researchers can do this type of research.”
This means that there is more research into how epigenetic changes could be used for diagnosing cancer and learning about prognosis, as well as how they could be targets for new treatments.
Patterns of changes may point to diagnosis
Each single epigenetic change on its own may be small, but as they accumulate, patterns – and disease – can emerge. Using genetic technology, researchers can scan genes in cancer cells and look for areas with concentrations of epigenetic changes and compare these areas with healthy cells to find distinct patterns that could be used to help diagnose cancer.
In some cancers, specific forms of non-coding RNA are more common than in healthy cells, whereas in other cancers, histone changes (both the type and the specific location of the change) or DNA methylation are different. By comparing cancer cells with healthy cells or with cancers with known outcomes, researchers can identify patterns that may be useful for diagnosis or prognosis.
Colorectal cancer is one cancer known to be highly influenced by epigenetic changes, and many researchers are looking for ways to use epigenetics for diagnosis. For example, researchers have found that levels of specific non-coding RNAs are higher in colon cancer cells than healthy cells. They are now testing whether simple blood tests to measure these RNAs can reliably detect colorectal cancer. Other blood tests are being developed that use DNA methylation on a specific gene as a way to diagnose colorectal cancer. While these tests show promise, they are not as sensitive as current screening or diagnostic tools, such as stool tests or colonoscopies.
Epigenetic changes are also often found in brain cancers. Dr Hawkins, who specializes in pediatric brain cancers, is currently leading a CCS Impact Grant studying epigenetic changes in a childhood brain stem tumour called diffuse intrinsic pontine glioma (DIPG) and whether these changes could be used for diagnosis.
Using their large database of tumour samples and patient outcomes, her team was able to identify a histone change in certain brain cells that is critically important to this cancer, along with the genetic mutation that leads to this change. While DIPG cells have a large number of epigenetic changes, many of them can be traced back to this one mutation. The team also found that children who had the mutation fared much worse in the long-term compared to those who didn’t have it.
“We still have a lot to learn about the biology of this mutation and the resulting histone change,” says Dr Hawkins. “But learning its importance to this cancer is a big step forward.”
Her team also developed a clinical test that can look for this mutation, which could be used to diagnose patients using small amounts of tumour tissue.
Treatments could reverse epigenetic changes
Epigenetic changes add an extra layer of complexity to our understanding of cancer, but they also offer the potential to be targeted with treatments that may stop cancer at its roots.
Epigenetic changes often affect genes that drive cancer growth, but unlike mutations in the DNA sequence that are hardwired into the cell and are difficult to change, epigenetic processes can be reversed by interfering with the biochemical reactions that cause them to attach to genetic material in the first place.
“There’s no known drug that can selectively target the genetic machinery involved in cancer cell replication,” says Dr Lehnertz. “But we might be able to use drugs to target the processes behind epigenetic changes in cancer.”
Both DNA methylation and histone modifications need specialized proteins called enzymes to attach or remove the chemical groups. Researchers have found that it is feasible to use drugs to interfere with these enzymes. In fact, drugs targeting both DNA methylation and histone modifications have already been approved by the Food and Drug Administration in the US and by Health Canada, mostly to treat different kinds of blood cancers. “DNA and histone-modifying enzymes are critical for ensuring that genes are expressed at the right time and place, and researchers have been able to develop compounds that interfere with these types of activities,” says Dr Lehnertz. “It’s exciting that we might be able to target these enzymes and reverse some of the epigenetic misregulation that occurs in cancer.”
Using epigenetic drugs in combination with other therapies has the potential to be particularly effective at stopping cancer growth at the genetic level and eliminate existing cancer cells at the same time.
The challenge with current versions of these drugs is that they can impact methylation or histone changes across all genes, including where they are necessary and not just at the locations that are problematic. “Right now, epigenetic targets are pretty broad-reaching,” says Dr Hawkins. “We’re going to need to improve drug development in order to target these changes more specifically.”
Dr Lehnertz is part of a CCS-funded team led by Dr Guy Sauvageau studying epigenetic changes that take place in acute myelogenous leukemia (AML). With their CCS research grant, they are studying a type of histone modification that is frequently altered in AML as a result of recurring genetic mutations. The team previously learned that a small group of people with leukemia carry mutations at the exact site where this epigenetic modification occurs. Interestingly, these patients do not seem to respond as well to standard chemotherapy as those without the mutation.
Now, the team will be studying how changes in histone modifications and accompanying gene mutations are connected and whether drugs that can reverse these changes could be an effective treatment for AML.
“This represents a new approach in leukemia, trying to make sense of both the genetic mutations and epigenetic patterns we see,” says Dr Lehnertz. “Through our work, we hope to first classify leukemias based on their specific epigenetic changes to get a more specific diagnosis, and then try to develop targeted and specialized treatments for the disease.”
Our view of cancer is constantly changing, and while research reveals new information about how cancer develops, it also raises more questions. Epigenetics adds a layer of complexity to our understanding of cancer – it’s not simply about genetic mutations as we once thought. And this additional layer of change can affect not just how cancer develops, but also how it responds to treatment and whether it is likely to relapse.
Recent studies show that targeting epigenetic changes has the potential to be a very successful strategy to diagnose, classify and treat some forms of cancer. But there are still many questions to be answered. Chief among them is the specificity of epigenetic-targeting treatments. Because these epigenetic changes can happen anywhere on DNA and are necessary for proper cell functioning, it’s important to target only the epigenetic changes that produce harmful consequences.
Epigenetic changes do not happen in isolation, and it’s likely that they are also having an impact on how the immune system responds to cancer and even how cancer cells become resistant to drugs. With more research, it may be possible to develop combination treatments that can tackle these multiple challenges together.
As we make a shift to more precise cancer therapies, doctors may have to consider epigenetic changes when they are making decisions about treatment. While it adds more complexity, there’s also potential for even greater personalization and a whole new field of exciting possibilities for treatment.
Eileen Hoftyzer, B.Sc.