Mutation Rate In A Gene On The X Chromosome Holds Promise For Testing Cancer Risk

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

"The mutation rate is widely believed to be a critical factor in thedevelopment of cancer, but it has been extremely difficult to study inhuman cells," says Dr. Araten. "The ultimate goal of our project is todevelop a test for the mutation rate. If successful, we may be ableidentify individuals at high risk for cancer and find ways to decreasetheir risk."

In the new study, supported by a grant from the Doris Duke CharitableFoundation, Dr. Araten found that the chance of a mutation in the PIG-Agene each time a cell divides ranges from about 1 in 3 million to about1 in 300,000 in cells from individuals without a genetic predispositionto cancer.

Among some people with Fanconi anemia and ataxia telangiectasia,conditions involving defects in DNA repair, which predisposes them tocancer, the probability of mutations was close to 1 in 100,000 to 1 in20,000 per cell division, according to the study.

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

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

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

Dr. Araten recently joined NYU School of Medicine. The study wasconducted at Memorial Sloan Kettering Cancer Center in the DepartmentsHuman Genetics and Molecular Pharmacology.