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A mutation in the ATM gene may increase the risk of breast cancer
  
By Bijal P. Trivedi

Dutch women who carry a mutation in one of two copies of a gene called ATM may be up to nine times as susceptible to breast cancer as women with two normal copies of the gene, according to a study published in the recent issue of American Journal of Human Genetics.

The 82 women chosen for the study were diagnosed with non-familial breast cancer before age 45 and had survived an average of fifteen years after diagnosis. Seven of these women, or 8.5 percent, had mutations in the ATM gene. By contrast, ATM mutations appear in less than 1 percent of the healthy Dutch population. The high rate among women with the ATM mutation suggests that the faulty gene may increase the risk of breast cancer.

But a close look at a subset of the study group suggests that a mutated ATM gene still requires a trigger to initiate breast cancer. Thirty-three of the women developed a second tumor in the other breast at least five years after the first tumor was diagnosed and treated with radiation. Four of these women, or 12 percent, carried the ATM mutation.

These results support the idea that radiation may induce tumors in women with the ATM mutation, says Laura J. van't Veer of the Netherlands Cancer Institute, and an author of the study. The 82 women all received small doses of radiation during childhood while being screened for tuberculosis, and again during treatment for breast tumors.

Normally, the ATM gene codes for an enzyme that detects DNA damage caused by radiation and signals a slew of repair enzymes-like a roadwork crew—to fix breaks in DNA or destroy the cell. Mutations in the ATM gene prevent the enzymes from gathering. Damaged DNA goes un-repaired, causing mutations in other genes to accumulate.

A mutation in both copies of the ATM gene causes ataxia telangiectasia, a genetic disorder that affects the immune and nervous systems. Children with this disease are particularly susceptible to developing cancer, especially leukemia, brain and stomach cancers.

It is too soon to claim that ATM increases the risk of breast cancer, contends Yossi Shiloh, of the Weizmann Institute of Science in Israel. This debate has been going on for a couple of decades, he says, and the results are not conclusive at this time.

The uncertainty arises because each of several studies has focussed on breast cancers with differing characteristics—age of onset and survival—and these observations are in groups with different ethnic, and thus genetic, backgrounds. While ATM mutations might increase the rate of early-onset breast cancer by an alarming nine-fold in Dutch women, says Shiloh, "the same mutation may have a different effect in other populations, so we need to look at results from many different countries."

Over the next two years van't Veer will compare two groups of Dutch breast cancer patients: women carrying an ATM mutation and treated for a first breast tumor with radiation and women carrying an ATM mutation but treated for the first tumor with surgery only. She hopes to further bolster her contention that the ATM mutation makes women more vulnerable to radiation. If her hypothesis holds up, it could mean that women should be screened for a mutation in ATM before undergoing therapeutic or diagnostic radiation, van't Veer says.

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Broeks, A. et al. ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet 66, 494-500 (February, 2000).
 

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