Preventing Genetic Glitches
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By Rabiya S. Tuma

Preventing Genetic Glitches

Changes in DNA function can alter cancer risk

By Rabiya S. Tuma


Researchers have known for decades that variations or mutations in critical genes can lead to cancer. More recently, geneticists have found that another type of genetic glitch can also promote tumor formation. These changes, called epigenetic modifications, do not alter the nucleotide sequence of DNA the way a mutation does, but rather they alter the way DNA functions by changing how it is packaged within a chromosome. “There is an interest in cancer prevention because we know that these epigenetic changes occur very early in the genesis of a tumor,” says Peter Jones, the director of the University of Southern California/Norris Comprehensive Cancer Center in Los Angeles and a past-president of the American Association for Cancer Research. “Obviously they are a target for prevention.”

The most common epigenetic change, DNA methylation, occurs when an enzyme attaches a small chemical group to specific spots in the DNA. When several methylations occur within a relatively short region of DNA, the cell packages that region of the chromosome more tightly than normal. The tight chromosome packaging hides the DNA from the enzymes that would normally read it, and thus switches off the genes in that part of the chromosome. Cancer geneticists have found that many tumor suppressor genes are silenced by DNA methylation in precancerous growths and tumors. Without the activity of these genes, cells turn cancerous.

To illustrate the impact epigenetic changes can have on cancer formation, James Herman, a medical oncologist who studies epigenetics at Johns Hopkins University School of Medicine, in Baltimore, points to the E-cadherin gene. A mutation in the gene is associated with a familial form of gastric cancer. Individuals in the affected families are born with one mutated E-cadherin gene and one normal copy. They remain cancer-free, unless some of their stomach cells lose the function of the normal copy of the gene—either through a mutation or epigenetic silencing. Once a gene is epigenetically silenced in a cell, that modification is passed on through subsequent cell divisions, so the gene will be shut off in all the daughter cells as well. However, cancer biologists have discovered the enzymes that are required to copy those methylations during DNA replication, and they have identified a number of drugs that inhibit those enzymes. In fact, two methylation inhibitors are already used to treat patients with blood cancers. More are being tested.

Animal models suggest the reversal or the limiting of epigenetic modifications in precancerous tissues could prevent tumor formation altogether. For example, in a study published in the September issue of Cancer Prevention Research, Jones and his colleagues reported that mutant mice that are predisposed to get intestinal tumors develop fewer of them after receiving regular doses of a drug that blocks DNA methylation.

“So we have a proof of principle in the mouse model,” Jones says. He notes, however, that current drugs that stimulate demethylation, including the agent his team used in the mouse study, are not sufficiently safe to use for preventing disease in humans. Jones has co-founded a company, TherEpi, which is trying to make better demethylating agents. Safer drugs, dietary supplements, or natural products are needed.

But even without those hoped-for agents, Herman is optimistic about the expanding knowledge of investigators regarding epigenetics and its role in cancer formation. “We are understanding more about the changes that occur during the development of cancer, and when they occur,” he says. “I think that will help us better assess the risk of patients for progressing to cancer. And the more someone knows about their risks, the more informed they are about considering chemoprevention approaches, and figuring out the risk-benefit ratios.”