New findings over the past five years suggest that epigenetics, a natural process in organisms, could be an important factor behind how cancers arise, proliferate, and reappear. It could also herald the beginning of a new series of therapeutic interventions to prevent or treat cancer.
The word ‘epigenetic’ literally means ‘in addition to changes in genetic sequence’. It includes any process that alters gene activity without changing the underlying DNA sequence, and which leads to modifications that can be transmitted to daughter cells. Epigenetic processes are essential to many organism functions, but many types of epigenetic processes have been linked to an increased risk of cancer and many other adverse health conditions.
To better understand epigenetics, we need to know the meaning of several related terms in genetics, such as genome and phenotype. Genome refers to the complete set of genes or genetic material that is present in a cell or organism, and carries all the genetic information of an organism. Phenotypes are the observable physical properties of an organism, including its appearance, development, and behavior.
An organism & phenotype is determined by its genotype, which is the set of genes the organism carries, as well as by environmental influences upon these genes. For instance, twin siblings who share identical genotypes, ultimately express nonidentical phenotypes because each twin encounters unique environmental influences as they develop. Epigenetics is thus the study of stable phenotypic changes that do not involve alterations in the DNA sequence.
Despite the human genome being sequenced in 2003, a clearer understanding of the genetic mechanisms and the working of our genome has remained elusive. This is largely because, while the DNA in genes encodes the information that allows us to develop, grow and repair our cells and tissues, the expression of the genes is
controlled by other mechanisms and their interaction.
Gene expression is the process by which information encoded in a gene is used to either make RNA molecules that code for proteins or to make non-coding RNA molecules that serve other functions. For genes to be expressed, they first need to be read, or transcribed, and then the molecules they code for are 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.
Researchers at the Institute of Cancer Research in the United Kingdom have now found that how the DNA is wound around proteins called histones, and how these are then packed into fibers called chromatin can affect the expression of genes.
Explaining their finding, the scientists noted that if the DNA is in a tangled portion of the genome, those genes may not be accessible to extract, and they are turned off. Whereas if they are in untangled regions in the DNA, then the genes can be expressed.
This finding 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. Earlier it was believed that cancer was the result of gene mutations in the cell, however, the new study shows that besides mutations on the genome that drive cancer, the epigenetic environment in which they exist is also a factor.
For their study the scientists sequenced the entire genome of 30 colorectal cancers that had not spread and eight adenomas (tumors that are not cancers). They also examined the accessibility of chromatin and the genes that were being expressed.
The study found mutations in the genes that coded for proteins regulating the transcription of chromatin, on the cancers but not on the adenomas. They also found these changes were passed on following cell division.
To look at why the genetic expression of cells from the same tumor can be different, another study sequenced the genome of different cells in the same tumor, as well as quantified the expression of all the genes in those cells.
This study found that less than 2 percent of differences in genetic expression in cells was due to differences in the DNA, which suggested that the differences could be due to epigenetics.
While the cancer death rate has decreased in the US and elsewhere in recent years, secondary cancers, which are cancers that can arise years after the initial cancer was treated, are still a conundrum. The lack of understanding about mechanisms that bring cancer out of dormancy has made them particularly difficult to treat.
Researchers are interested in understanding why breast cancer, for example, can relapse 20 years after surgery.
New studies now show that dormancy, when the tumor cells are doing nothing in the body of a person with breast cancer, could be due to epigenetic factors, and when or if the tumor becomes active is also determined by epigenetics. In terms of cancer biology, the big question is, can we exploit epigenetic changes for developing new treatments by stopping the tumor from evolving by identifying epigenetic vulnerabilities.
While epigenetics of cancers are challenging to investigate, they may well hold the key to understanding where our failures to prevent and treat cancers are coming from.
