Epigenetics is a conceptually and practically challenging area of research. However, work over the past 5 years has suggested it could be behind many of the remaining questions we have about how cancers arise, proliferate, and reappear.
Nearly 2 decades since the human genome was sequenced for the first time, in 2003Trusted Source, there are still many questions that remain about how our genomes work.
While sequencing the human genome has provided an enormous amount of insight into the ways our cells and bodies work, a clear understanding of the genetic mechanisms underpinning many common diseases and our health has remained elusive.
One reason for this is that while our DNA encodes the information that allows us to develop, grow and repair our cells and tissues, the expression of our genes is controlled by other mechanisms. For our genes to be expressed, they first need to be read, or transcribed, and then the molecules they code for made, or translated.
For the cell machinery to be able to read the DNA, the DNA itself needs to be accessible. This is affected by a number of mechanisms, and it is becoming increasingly clear that the way in which the DNA is wound around proteins called histones, and how these are then packed into fibers known as chromatin plays an important role.
Prof. Trevor Graham, professor of genomics and evolution at the Institute of Cancer Research (ICR) in London, told Medical News Today in an interview that “depending on how [DNA is] folded, that can affect the expression of genes.”
“Logic is that if the DNA is all tangled up, and closed in a great tangled portion of the genome, those genes may not be accessible to machinery to extract, and they’re turned off. Whereas if they’re in untangled regions in the DNA, then the genes can be expressed,” he explained.
This is a form of epigenetic control, as the expression of a gene varies, not due to a change in the actual DNA sequence, but due to other processes that affect its accessibility.
Mutations vs. epigenetics
Historically we have thought of cancer as the result of an accumulation of mutations in the cell. Much focus has been on the environmental causes of cancerous mutations that increase an individual’s risk of developing certain cancers.
Prof. Luca Magnani from Imperial College London, chair in cancer adaptation and evolution, explained to MNT in an interview:
“We kept sequencing, just the coding region[s], because those are always easy to explain. Right? So the idea of a mutation-causing cancer is something that everybody understands. But I think, you know, we probably hit the glass ceiling on those a while ago.”
One of the potential reasons for the fact that questions still remain about the role of DNA changed in cancer, is that it is not just the mutations on the genome that drive cancer, but the epigenetic environment in which they exist.
In other words, a gene can only be transcribed where the chromatin structure and other epigenetic mechanisms allow it to be so.
Profiling this chromatin structure alongside the sequence of the cancer genome was the focus of research recently published in Nature by a team from the ICR, involving both Prof. Graham and Prof. Magnani, alongside a large number of other researchers, headed up by Prof. Andrea Sottoriva and postdoctoral researchers Dr. Timon Heide and Dr. Jacob Househam.
Mapping the epigenome of tumors
In the first study recently published in NatureTrusted Source, the team sequenced the entire genome of 30 colorectal cancers that had not spread and eight adenomas, alongside profiling the accessibility of chromatin and the genes that were being expressed.
They found mutations in the genes that coded for proteins regulating the transcription of chromatin on the cancers and not on the adenomas. They also found these changes were passed on following cell division.
These changes in the chromatin happened near the position of mutations on genes that are known drivers of cancer, in the cells taken from cancerous tumors.
To look at why the genetic expression of cells from the same tumor can be different, another study whose results appeared in NatureTrusted Source sequenced the genome of different cells in the same tumor, as well as quantifying expression of all the genes being expressed in those cells.
It found that no less than 2% of differences in genetic expression in cells was due to differences in the DNA, leading to the suggestion these differences could be due to epigenetics.
Corresponding author Prof. Graham said: “I think one of the most striking things is that we find examples of genes, which we know from the literature from previous research that are important for cancer development. And we found that they change the chromatin accessibility.”
“So they could either get turned on if they were [a cancer-causing] protein or turned off [if] they were a [tumor] suppressor gene by changing the chromatin, but that happened without any DNA mutation. So it suggested changes in the epigenome themselves, could lead to cancer development, without being a mutation,” he further explained.
Methylation and cancer
While these papers looked at the role of chromatin in the genetic expression of cancers, there are other laboratories looking at the role of methylationTrusted Source, another epigenetic process by which a gene can be turned on or off, in cancer. Cancer cells are known to have different methylation patterns compared to other cells.
Research is focused on determining if cancer can be detected in different parts of the body by looking at cell-free DNA in the blood or cells taken from tissues that are more easily accessed than the place where cancer might be.
One example of this is the WID-CIN test, which is done alongside routine HPV testing carried out to determine the risk of a woman developing cervical cancer within 5 years.
The WID-CIN test looks at methylation patterns of cells collected during routine cervical cancer screening in order to determine which women who test positive for HPV are likely to develop cancers in the following years.
A study of women in Sweden published in Genome Medicine in October 2022 showed that it correctly identified 55% of women who were HPV positive who went on to develop cervical cancer 1–4 years after the test.
Not only have Prof. Martin Widschwendter and his team shown that mapping the methylation of cells taken from the cervix can predict cervical cancer, they have also shown that it can be used to detect ovarianTrusted Source, endometrial, and breastTrusted Source cancers, too.
There is also the ongoing GRAIL project that seeks to determine if cancers can be detected from the methylation patterns of cell-free DNA found in the blood.
This project has mapped the methylation of the cell-free DNA and developed algorithms to determine if there are patterns that can be detected not only from cancer, but if these patterns can show which part of the body the cancer is in.
While chromatin and methylation changes are different processes that affect how the DNA is read, there is some suspicion they could interact, particularly in cancer cells.
Prof. Graham told MNT: “They are interrelated. So regions of close chromatin, where the accessibility is low, and inside of tangles of DNA, that DNA tends to be methylated. And so there’s an interrelationship there between DNA methylation and chromatin accessibility.”