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Study Suggests DNA Methylation Caused By Environmental Factors Leads to Cancer

Study Suggests DNA Methylation Caused By Environmental Factors Leads to Cancer
Epigenetic finding could have future impact in treatment of the disease
M. D. Anderson News Release 05/14/02

Researchers at The University of Texas M. D. Anderson Cancer Center have discovered that environmental factors - such as lifestyle, diet and geographical location - can affect the DNA methylation status of genes in a person's normal tissue, potentially leading to pre-cancerous or cancerous conditions.

The study is published in the May 15 issue of the Journal of the National Cancer Institute.

Dr. Jean-Pierre Issa, associate professor in M. D. Anderson's Department of Leukemia, is the article's lead author and the study's principal investigator. According to Dr. Issa, there has been growing interest and research over the past decade to suggest that in terms of a person's DNA heritage, gene mutation is not the only event responsible for cancer. Other non-mutation events also can lead to development of the disease.

DNA methylation, the addition of methyl groups on one of the bases of DNA, is a biological process that normal DNA goes through after each replication. The process plays a central role in gene expression. According to Dr. Issa, alterations in the DNA methylation process, due to abnormal addition of methyl group tags, can result in uncontrolled cell division and have a direct correlation to tumor genesis.

"The study of epigenetic changes such as methylation has emerged as a relatively new and important way by which we study how cancers arise, happening in parallel and/or in addition to gene mutations," says Dr. Issa, who is also the chief of the section of translational research in M. D. Anderson's Department of Leukemia.

"Methylation is not picked up by a standard mutation screening because it does not change the primary structure of DNA; it just changes the decoration on DNA, which, in turn, determines the way the DNA is going to be used."

In their research, Dr. Issa and his colleagues focused on liver cancer because of the disease's direct correlation with environmental agents - alcohol, cirrhosis, hepatitis and geographical variation - thereby serving as a ideal example to determine whether environmental carcinogens are associated with methylation of multiple genes.

Using a specific methylation assay, the M. D. Anderson researchers examined the methylation status in 85 liver cancer tumors in patients from specific regions of the world. Forty patients were from either China, East Asia or Egypt, locations with a high incidence of the disease; 45 patients were from the United States, the United Kingdom and/or other areas of Western Europe, all areas with relatively low incidence rates of liver cancer.

Researchers observed pronounced differences in environmental factors between the "high risk" and "low risk" groups: viral hepatitis B and/or C, cirrhosis of the liver and p53 gene mutations were all found at a higher rate in the specimens from the "high-risk" group. Analysis was then performed to determine whether these risk factors were directly associated with DNA methylation.

"Our research concluded that there was a much higher incidence of irregular DNA methylation in patients from the 'high-risk' group whose tumors were exposed to the environmental exposures associated with the disease compared to those patients from the 'low risk' group, whose tumors were more likely to have developed spontaneously," says Dr. Issa.

Dr. Issa feels that this scientific discovery has the potential to influence how agents are classified as carcinogens, and one day directly affect the treatment of cancer patients, with therapies already under investigation at M. D. Anderson.

"In terms of therapy, preliminary studies have suggested that methylation can be reversed via a specific groups of drugs that have been around for quite some time but were only found to affect methylation in the 1990s. Actually, we have done a study in leukemia showing promise that methylation can be reversed," he says.

"This is a whole new exciting area of study that hopefully in the not too distant future can be examined beyond the field of leukemia to solid tumor cancers to determine whether patients with cancers associated with environmental factors - and thereby methylation - might benefit from adding these drugs to their standard of care."

05/14/02


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