The study of epigenetics presents both philosophical and practical difficulties. However, research conducted over the previous five years has indicated that it might be to blame for a lot of the unanswered questions regarding how cancer develops, spreads, and reappears.

Many unanswered issues regarding how our genomes function still exist nearly 20 years after the human genome was initially sequenced, in 2003Trusted Source.

A thorough knowledge of the genetic pathways underlying many common diseases and our health has remained elusive, even though mapping the human genome has given us a great deal of insight into how our cells and bodies function.

One explanation for this is that, while our DNA contains the instructions necessary for our cells and tissues to develop, grow, and heal, other processes regulate how our genes are expressed. Our genes must first be read, or transcribed, for them to be expressed, and then the molecules they code for must be produced or translated.

The DNA must be accessible for the cell's machinery to be able to read it. It is becoming more and more obvious that the method in which the DNA is twisted around proteins called histones and how these are subsequently packed into fibres known as chromatin plays a significant part in this. This is influenced in several ways.

According to Prof. Trevor Graham, professor of genomics and evolution at the Institute of Cancer Research (ICR) in London, "how [DNA is] folded might alter the expression of genes," according to a Medical News Today interview.

According to logic, some genes may not be available for machinery to extract if the DNA is completely entangled and closed in a large, tangled region of the genome. As a result, they may be switched off. The genes can be expressed, though, if they are in untangled DNA sections, he said.

This is an example of epigenetic control because various processes that impact a gene's accessibility rather than a change in the gene's actual DNA sequence affect how a gene is expressed.

Epigenetics vs. mutations

In the past, we have believed that an accumulation of cell mutations causes cancer. The environmental factors that contribute to malignant mutations and raise a person's chance of getting some types of cancer have received a lot of attention.

In an interview with MNT, Prof. Luca Magnani, chair in cancer adaptability and evolution at Imperial College London, explained:

We continued to sequence only coding regions because these are always simple to explain. Right? So, everyone is aware of the concept of a mutation producing cancer. However, I believe that we likely reached the ceiling for those a while ago.

There are still some unanswered questions regarding the significance of DNA changes in cancer, which may be related to the fact that epigenetic factors as well as genetic abnormalities play a part in the development of the disease.

In other words, chromatin structure and other epigenetic mechanisms must be present for a gene to be transcribed.

A team from the ICR led by Prof. Andrea Sottoriva and including Prof. Graham, Prof. Magnani, a large number of other researchers, postdoctoral researchers Drs. Timon Heide and Jacob Househam, and Prof. Magnani's work were recently published in Nature with the goal of profiling this chromatin structure alongside the sequence of the cancer genome.

mapping the tumor epigenome

The scientists sequenced the whole genomes of 30 colorectal tumors that had not spread and eight adenomas in the first study, which was just published in Nature Trusted Source. They also profiled the accessibility of chromatin and the genes that were expressed.

On the malignancies but not on the adenomas, they discovered alterations in the genes that encoded proteins regulating the transcription of chromatin. Additionally, they discovered that during cell division, these modifications were passed on.

In the cells collected from malignant tumours, these chromatin alterations occurred close to the location of mutations on known cancer-causing genes.

Another study whose findings were published in NatureTrusted Source analysed the genomes of various tumour cells and quantified the expression of every gene in those cells to examine why the genetic expression of cells from the same tumour can vary.

It was suggested that these variations may be caused by epigenetics after it was shown that at least 2% of variations in genetic expression in cells were caused by variations in the DNA.

"I believe one of the most remarkable things is that we uncover examples of genes, which we know from the literature from past studies that are critical for cancer development," corresponding author Prof. Graham stated. We also discovered that they alter chromatin accessibility.

Therefore, by altering the chromatin, they could either be switched on if they were [a cancer-causing] proteins or turned off [if] they were [a tumour suppressor gene], but this occurred without any DNA mutation. Therefore, it implied that changes in the epigenome could cause cancer without being a mutation, he continued.

Malignancy and methylation

While these publications examined the function of chromatin in the genetic expression of malignancies, other research centres are examining the function of methylation, another epigenetic process that regulates the on/off switch for genes, in cancer. It is well known that cancer cells differ from other cells in their methylation patterns.

Cell-free DNA in the blood or cells obtained from tissues that are easier to access than the area where cancer maybe is the focus of research to see if cancer can be identified in various places of the body.

One illustration of this is the WID-CIN test, which is used in conjunction with routine HPV testing to assess the likelihood that a woman would get cervical cancer within the next five years.

When a woman tests positive for HPV, the WID-CIN test analyses the methylation patterns of cells obtained during standard cervical cancer screening to identify those who are most likely to develop cancer in the years to come.

According to a study of Swedish women published in Genome Medicine in October 2022, 55% of those who tested positive for HPV and went on to acquire cervical cancer between 1-4 years following the test were appropriately detected.

Prof. Martin Widschwendter and his group have demonstrated that mapping the methylation of cells obtained from the cervix can not only predict cervical cancer, but also be used to identify ovarian, endometrial, and breast malignancies.

The GRAIL research, which is still active, aims to find out whether malignancies may be recognized by the methylation patterns of cell-free DNA present in the blood.

As part of this effort, the methylation of cell-free DNA has been mapped, and algorithms have been built to see whether any patterns may be used to identify not only cancer but also the location of cancer in the body.

There is some speculation that chromatin and methylation alterations, which influence how the DNA is read, may interact, especially in cancer cells.

According to Prof. Graham, they are connected. Therefore, DNA tends to be methylated in areas of tight chromatin where accessibility is minimal and inside DNA tangles. Therefore, chromatin accessibility and DNA methylation are related to one another.

"I believe what's intriguing is that we're not sure whether DNA tangles up because it becomes methylated or the other way around. What happens to the other if we modify a tangle or the methylation, then? It will be incredibly interesting to look at some of those dynamics.
- Trevor Graham, professor

Awakening cancer from its dormant state

According to the Centres for Disease Control and Prevention (CDC), the death rate from cancer has been falling over the past few years. However, secondary malignancies, which are cancers that can develop many years after initial cancer has been treated, continue to be a mystery.

Because we have such a limited understanding of the mechanisms that cause cancer to awaken from its dormant state, the disease is notoriously difficult to treat.

In an interview with MNT, Professor Magnani stated, "My lab is highly interested in understanding why certain cancers, including breast cancer, might recur 20 years after surgery." And we believe that all of these hidden phases that we call dormancy, so when these tumour cells are doing nothing, they are just sitting like dying, in the body of women, we think that all of that is epigenetic, and when the tumour goes off, so when the tumour awakens, we also believe that that transition is purely epigenetic. "And we believe that all of these hidden phases that we call dormancy, so when these tumour cells are doing nothing, they are just sitting like dying

The most recent studies published in Nature focused mainly on primary malignancies; but, according to Prof. Magnani, the next most important subject may be the function of epigenetics in secondary tumours.

"In terms of cancer biology, I believe the most important question is whether or not it is possible to take advantage of epigenetic modifications in the context of new treatments. Because I believe that essentially what we want to accomplish is to stop the tumour from having the capability of evolving, and we want to do this as soon as possible. Consequently, I believe that a lot of individuals are attempting to identify epigenetic vulnerabilities.

— Associate Professor Luca Magnani

"Is it the case, for instance, that cancer cells are more dependent on particular epigenetic alterations than normal cells? You could start doping these processes if that were the case, which is something to keep in mind. According to his statement, "I believe that is like the largest question at the moment."

Epigenetics of cancers are more difficult to investigate than DNA mutations, which can now be found using whole genome sequencing, which is less expensive and more readily available. However, they may very well hold the key to understanding where our failures to prevent and treat cancers are coming from. DNA mutations can now be found using whole genome sequencing.