For many women who have a strong family history of breast cancer, knowing whether they have inherited gene mutations that predispose them to the disease is key to their ability to manage their fears of developing cancer.
But for more than half the women in this category, no genetic test is available because their family disease is caused by something other than known BRCA1 or BRCA2 mutations, the primary mutations so far unearthed in severely affected families.
For the past several years, research teams around the world have been scouring the genes of these families with little success. "Our nightmare is that there will be 20 or more genes, each accounting for a small fraction of these families," a scenario that will make it very difficult to isolate these genes by the methods that yielded BRCA1 and BRCA2, said David E. Goldgar, Ph.D., of the International Agency for Research on Cancer in Lyon, France.
The next best approach is to scrutinize genes that for one reason or another have been implicated in breast cancer. Now it seems that this approach has borne fruit. An Australian study has uncovered mutations in a gene long suspected to raise the risk of breast cancerthe gene that underlies the hereditary disease ataxia-telangiectasia.
These mutations are associated with a risk of breast cancer as high as that seen for mutations in BRCA1 and BRCA2, and studies have suggested that they account for breast cancer cases in about 3% of severely affected Australian families whose hereditary disease cannot be accounted for by mutations in other genes.
Study director Georgia Chenevix-Trench, Ph.D., said she believes that further searching could push that figure up to 20%.
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Ataxia telangiectasia (A-T) is primarily a neurological disease that results from inheriting a defective copy of the ATM gene from each parent. Alert parents pick up signs of the disease when their toddlers stumble; by age 10 affected children are often wheelchair bound. Geneticist Michael Swift, M.D., at the Institute for the Genetic Analysis of Common Diseases at New York Medical College in Hawthorne, N.Y., has studied these families for more than 30 years. Early on, he noticed that the mothers of children with A-T, carriers of a single copy of the defective gene, often developed breast cancer.
Swifts team decided to put that suspicion to a more rigorous test and began tracking the course of cancer in A-T families. In 1991, his group published the result: Cancers of many types were more frequent in A-T families, and breast cancer stood out as the most common. "It was clear we had a breast cancer gene," Swift said.
With ATM mutation carriers constituting about 1% of the population, the potential contribution to breast cancer could have been as high as 10% of all cases. But, although women carrying an ATM mutation appeared to be at increased risk of breast cancer, Swift and others believed that the increased risk would be something on the order of four to fivefoldnot the sort of deadly predisposition that leads to mothers, daughters, and sisters all developing the disease. In other words, families with multiple cases of breast cancer were unlikely to carry an ATM mutation. Rather, it was thought that these mutations would crop up among women who did not have a family historyso-called sporadic cases.
With the cloning of the ATM gene in 1995, researchers began testing Swifts prediction to see how often the readily detectable mutations that had been shown to cause most cases of A-T were actually involved in sporadic cases of breast cancer. Results were conflicting. Some studies suggested that the mutations were prevalent among women with breast cancer; others did not. While many researchers were ready to believe that mutations of the ATM gene might raise the odds of developing breast cancer, few believed that ATM mutations could underlie those extreme dispositions to breast cancer that create multiply affected families.
But two subsequent reports about more subtle mutations of the ATM gene raised the curiosity of Chenevix-Trench, who is based at the Queensland Institute of Medical Research and directs Australias familial breast cancer study, which is known as the Kathleen Cuningham Consortium for Research into Familial Breast Cancer, or kConFab. Chenevix-Trench wanted to find a genetic explanation for breast cancer cases in 147 families enrolled in the study. These families did not carry BRCA1 or BRCA2 mutations.
One report described a Scottish family with very mild A-T but with multiple cases of breast cancer. The mutation in the ATM gene in this family, known as "T7271G," changed only a single amino acid of the ATM protein. A second report described a group of 82 Dutch women with sporadic breast cancer. Three of these women had an ATM mutation referred to as "IVS106TG," which slightly shortens the length of the protein. Other work had shown that this mutation was the cause of classic A-T in a Turkish boy.
The kConFab researchers decided to test to see if these ATM mutations might account for breast cancer in some of their multiple-case families. They also tested for these mutations among a group of 500 women with breast cancer but not necessarily a family history of the disease.
The hunch proved right. Initially, out of 79 families, the Scottish mutation was identified in one family, the Dutch mutation in two. Since then, two more families have been found to carry the Dutch mutation. In all, five out of 147 severely affected families carried one of these two mutations in the ATM gene. The Australian study concluded that the presence of the mutations dramatically increased the odds of developing breast cancer to 16-fold, as high as that for some BRCA1 or BRCA2 mutations. (See article, p. 205.)
Only women with a family history appeared to carry these mutations. This finding contrasted with the Dutch study, which identified a high number of these mutations among sporadic casesa discrepancy that Trench suggested needs further exploration. However, at least in the Australian families, ATM mutations appear to be extremely severe and account for the occurrence of breast cancer in some 3% of families.
Chenevix-Trench said she believes that this conclusion may be the tip of the iceberg for ATM mutations and breast cancer. kConFab screened its families for only two specific mutations in the gene. Chenevix-Trench said she believes that up to 20% of all high-risk families might harbor a subtle mutation in the gene such as the Dutch mutation or the Scottish mutation.
Now Michael Strattons high-throughput mutation-detection operation at the Institute for Cancer Research in Sutton is gearing up to analyze the entire ATM gene from all the kConFab families to look for other mutations along the gene.
The biggest challenge in examining the relationship between ATM mutations and breast cancer, said Chenevix-Trench, "is proving that if you find a family carries a subtle change in their ATM gene, that this is truly the cause of their breast cancer, rather than a harmless variant of the gene."
In the case of the kConFab families, the researchers were able to show that the ATM mutation tended to be coinherited with breast cancer. Still, with the small number of families, the findings are not watertight. The women who carry these mutations still carry one good copy of the ATM gene, which ought to be enough to keep them healthy.
But Chenevix-Trenchs colleague Kum Kum Khanna, Ph.D., also at the Queensland Institute of Medical Research, has shown the proteins produced by the Scottish and Dutch mutant alleles pack a powerful punch; not only are they faulty themselves, but they also corrupt the function of the normal ATM protein. Normal ATM protein activates members of the DNA repair crewthe BRCA1, BRCA2, and p53 gene productsby adding phosphate groups to them. But in the presence of the mutant ATM, no phosphate is added. Khanna has also tested cells from the original Scottish and Dutch patients and found the same result, confirming that it is these same mutations rather than mutations in other genes that are at fault.
Swift said he believes that screening for the ATM gene will benefit patients. His recent findings show that, although A-T mutation carriers with breast cancer have a far worse prognosis than other breast cancer patients, they respond ninefold better to radiation therapy than women who do not carry the A-T mutation. "The A-T mutation is a natural radiosensitizer for these tumors," Swift said. But there are also concerns that radiating normal tissue of female carriers can trigger the cancer, since the gene is known to be vital to repairing radiation-induced DNA damage.
For Trench, the findings are added proof of the guilt of DNA repair pathway genes in hereditary breast cancer. Why breast cancer, as opposed to other cancers, is so vulnerable to defects in DNA repair genes remains a mystery. But, says Trench, "with over 30 genes involved in the DNA repair pathway, this shows us where we should be doing some serious exploration."
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