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Mutation rate in a gene on the X chromosome holds promise for testing cancer risk

September 16, 2005

A new study to detect an elevated rate of mutations in a gene on the X chromosome holds promise for developing a test that could identify individuals at risk for developing cancer. In the study, led by David J. Araten, M.D., Assistant Professor in the Department of Hematology at NYU School of Medicine, the rate of mutations in the gene, called PIG-A, was significantly higher in individuals born with defects in the cellular machinery to repair DNA compared to people without these genetic conditions.

The study is published in the September 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

"The mutation rate is widely believed to be a critical factor in the development of cancer, but it has been extremely difficult to study in human cells," says Dr. Araten. "The ultimate goal of our project is to develop a test for the mutation rate. If successful, we may be able identify individuals at high risk for cancer and find ways to decrease their risk."

In the new study, supported by a grant from the Doris Duke Charitable Foundation, Dr. Araten found that the chance of a mutation in the PIG-A gene each time a cell divides ranges from about 1 in 3 million to about 1 in 300,000 in cells from individuals without a genetic predisposition to cancer.

Among some people with Fanconi anemia and ataxia telangiectasia, conditions involving defects in DNA repair, which predisposes them to cancer, the probability of mutations was close to 1 in 100,000 to 1 in 20,000 per cell division, according to the study.

In order to find the mutations in the PIG-A gene, Dr. Araten took advantage of some unique properties of this gene that can be exploited with an instrument called a flow cytometer, which rapidly sifts through millions of cells to identify the rare mutants. This tool uses a laser to light up antibodies attached to surface proteins on cells; PIG-A mutants lack some of these proteins and do not fluoresce.

In human cells there are two functional copies for most genes and therefore two mutations would be required to identify a rare mutant. Because each mutation is so rare, two mutations would be unlikely to occur in the same cell in a screening test, making detection nearly impossible. However, the PIG-A gene is on the X-chromosome, which is present in only one copy in male cells and there is only one functional copy in female cells. Therefore, cells with only a single mutation in PIG-A can be identified.

"The higher the mutation rate, the more quickly cells will acquire the mutations that cause cancer," says Dr. Araten. "With a test for the mutation rate, we may be able to enroll patients at high risk in screening programs to identify cancers at an early, curable stage. We may also be able to develop medications that decrease the mutation rate."

New York University Medical Center and School of M