Tumor Epigenetics:
Changes in function but not in DNA

For decades, scientists and doctors assumed that cancer was caused by irreversible damage to some critical stretch of DNA within one's genome. But in the last few years, a much more complex picture has emerged, one that shows that some cancers are caused by epigenetic changes-tiny chemical tags that accumulate over time and can turn genes on or off. Unlike genetic damage, epigenetic changes can sometimes be reversed, and with treatments that are far less toxic to the patient.

The word "epigenetic" literally means "in addition to changes in genetic sequence." It is used to refer to any process that alters gene activity without changing the DNA sequence. Experiments show that epigenetic changes, unlike mutations, can be reversed.

Understanding cancer at the molecular level helps us understand better why cancers arise, because the things that could cause genetic damage might not be the same things that could cause epigenetic damage. It also helps us understand why some cancers may respond better to certain types of therapies. It could be that some drugs or some types of therapies work better for genetically damaged cancers, while others work better for epigenetically damaged cancers.

What causes epigenetic changes?

The short answer is aging. This remains somewhat of a mystery, but the unifying feature that could explain this epigenetic damage is the number of times a cell has divided. As we age our stem cells divide more and more to replenish tissue damage.

• Chronological age: As we age our stem cells divide more and more to replenish tissue damage opening the door for epigenetic changes.

Epigenetic damage (seen here in more widespread darker areas) accumulates as we age. The DNA on the left is from an eight-year- old, while the corresponding stretch of DNA on the right is from a 60-year-old.

• Biological age: The single unifying factor leading to epigenetic changes is tissue damage, inflammation, and the need for stem cells to repair that injury. Every time a stem cell has to repair injury, it is aging a little more.

		So a person who has been exposed to a lot of things that injure tissues (like exposure to sunlight) is a person who is biologically 'older' than a person who has never been exposed to things that injure tissues.
Image courtesy of of PBS, NOVA/WGBH Educational Foundation

Two types of epigenetic changes are described below:

1) Methylation

In this alteration, some parts of the DNA are modified by the addition of a methyl (-CH3) group to the base. A chemical reaction in which a small molecule called a methyl group is added to other molecules. Methylation of proteins or nucleic acids may affect how they act in the body. Methylation of DNA is associated with the inactivation of that particular region of DNA. Abnormal DNA methylation patterns have been seen in cancer cells. Methylation alters the expression of the affected genes.

• Methylation changes are thought to occur more frequently than mutations in the DNA, and so may account for many of the changes during neoplastic progression (the process in which normal tissue becomes cancerous), particularly in the early stages.

2) Acetylation

• In this epigenetic change, proteins which the DNA is wrapped around become modified by the addition of acetyl (-CH3CHO) groups.

		This image shows DNA wrapped around proteins called histones, shown here in green. When the histones squeeze the DNA tightly, they "hide" that section of genetic material from the cell. A gene that is hidden cannot be utilized. It is the same as having a dead gene or a mutated gene.
Image courtesy of of PBS, NOVA/WGBH Educational Foundation

Much remains unknown about the role of epigenetic factors and cancer. Since some epigenetic changes are reversible through modifications to genes or proteins that occur in the tumor and its microenvironment, companies are now looking to develop new treatments to target these areas.

Epigenetic Carcinogens:

A variety of compounds are considered epigenetic carcinogens (i.e., they result in an increased incidence of tumors), but they do not show DNA mutations. Examples include:

• Chromium: a metal


• Diethylstilbestrol (DES): a drug that was it was found to be damaging to fetuses when given to pregnant women.


• Arsenite: a salt or ester of arsenous acid


• Hexachlorobenzene: a fungicide formerly used as a seed treatment, especially on wheat, to control the fungal disease bunt


• Nickel compounds: nickel sulfide fumes and dust are believed to be carcinogenic, and various other nickel compounds may be as well. Nickel allergies affecting pierced ears are often marked by itchy, red skin. Many earrings are now made nickel-free due to this problem. It was voted Allergen of the Year in 2008 by the American Contact Dermatitis Society.

 

Epigenetic Treatments:

These drugs are often referred to as demethylating agents. This is still a new field so expect more drugs to become available on an ongoing bases.

Myelodysplastic syndrome (MDS):

• Azacitabine (Vidaza)


• Decitabine (Dacogen)


• Azacitabine has orphan drug status (The term orphan drug refers to a pharmaceutical agent that has been developed specifically to treat a rare medical condition).

Cutaneous T-cell lymphoma

• Vorinosat and is in clinical trials for a number of different cancers.

CISN Summary:

• Researchers now think that most cancers are a mixture of genetic and epigenetic changes. There is actually a lot more epigenetic change than genetic change in the majority of cancers.


• Research into epigenetics is proving to be important to understanding cancer biology.


• Epigenetic methylation is like putting on a glove. If your hand is a gene and you put a glove on, you cover up the hand (gene) and it can no longer be seen (function).