02 Sep 1996: NIH Scientists Find Mutant Repair Gene MSH3 Has Role in Uterine Cancer
Some endometrial cancers, or tumors in the uterus, appear to result from a mutation in a DNA repair gene, called MSH3, scientists at the National Institute of Environmental Health Sciences reported today in the journal Nature Genetics.
When impaired, the gene fails to correct errors that may occur in DNA, the genetic code of cells, the scientists said. These errors may result from environmental or chemical exposures and occur when the cell makes copies of its DNA for new cells.
These uncorrected errors, or genetic instability, can result in misspellings, unnecessary stuttering or deletions of the genetic code. This type of instability has been reported in many types of human tumors. Thus, in addition to the role of impaired MSH3 in endocrine cancer, the researchers said, it may play a role in these "other neoplasms that display microsatellite instability"-colon, pancreas, ovary, stomach, lung and bladder.
DNA is a long but stable molecule-an ideal substance to which Nature entrusts the genes of every species, individual animal or human, and individual cell. But instability may occur in the DNA's genetic code-and in the cell it controls-when radiation or an environmental chemical damages one or more genes on the DNA strand, permitting genes to shift.
Ordinarily, the NIEHS scientists said, the cell uses many repair genes to recognize the errors in the DNA much as a computer's spell check finds errors. But when this or other DNA repair genes have been impaired, the errors remain uncorrected. Over time, the accumulation of these errors can lead to cancer.
John I. Risinger of the NIEHS laboratory of molecular carcinogenesis and Asad Umar, Ph.D., of the NIEHS laboratory of molecular genetics contributed equally to the work reported today. They worked in human endometrial cancer tumors and human cell lines. NIEHS' Thomas A. Kunkel, Ph.D., director of the molecular genetic lab, and J. Carl Barrett, Ph.D., director of the molecular carcinogenesis lab and scientific director of the institute, are the senior authorson the paper. Risinger is also a graduate student of Dr. Barrett's at the University of North Carolina, Chapel Hill. Also involved in the study were Jeff Boyd, Ph.D., of the University of Pennsylvania Medical Center in Philadelphia, and Andrew Berchuck, M.D., of the division of gynecologic oncology at Duke University, Durham, N.C.
According to Risinger, "Mutations of the DNA mismatch genes MLH1 and MSH2 have been shown in hereditary endometrial cancer, whereas mutations of MSH3 appear to be involved in some of the 35,000 sporadic endometrial cancers that occur each year in the United States." The uterus is the fourth most common tumor site in women, after breast, lung and colon-rectal.
Dr. Umar said, "Knowing more about this process should help drug companies develop better cancer drugs."
Although Japanese scientists discovered MSH3 in 1989, its precise role had not been determined until this study, in which data provided new evidence of a role for MSH3 in DNA mismatch repair and cancer, the NIEHS scientists said. MSH3 joins five other genes now associated with DNA mismatch repair within human cells.
In the NIEHS study, a normal, healthy non-mutant MSH3 gene was added to endometrial cancer cells which had defective MSH3. The cells were once again able to repair DNA errors. "However," Dr. Umar said, "we're a long way from being able to make such a correction in a patient with uterine cancer-or to use any sort of gene therapy to treat tumors-though I wouldn't say that might not be possible someday in the future."
NIEHS is located in Research Triangle Park in central North Carolina between Raleigh, Durham and Chapel Hill and is one of the federal National Institutes of Health. A major thrust of NIEHS' basic research involves susceptibility-why some people are more susceptible to environmental factors and diseases they cause or trigger.
Scientist John Risinger can be reached at 919/541-2252 (work)
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