BioWorld International Correspondent

LONDON - A gene that is present in mutant form in about one in 200 of the population can double a woman's lifetime risk of breast cancer. The gene, called ATM, encodes a protein kinase that is involved in DNA repair.

The discovery brings to five the total number of genes identified as conferring an increased risk of breast cancer when mutated. All of them encode proteins involved in repair of double-stranded DNA breaks.

Michael Stratton, professor of cancer genetics at The Institute of Cancer Research and the Wellcome Trust Sanger Institute, told BioWorld International: "There are implications for therapy for the women who have breast cancers due to mutations in the ATM gene. Recent evidence has shown that certain drugs, such as the PARP inhibitors, may work much more effectively in tumors that arise in people with abnormalities in breast cancer predisposition genes."

The work is reported in the July 7, 2006, issue of Nature Genetics in a paper titled "ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles." Cancer Research UK, the Institute of Cancer Research and Breast Cancer Campaign funded the research.

In the UK, about one in 10 women develop breast cancer during their lifetime. Those who inherit mutant copies of the genes BRCA1 or BRCA2 have a much higher risk of developing breast cancer by age 70, at 70 percent. Together, those two genes account for between 20 and 25 percent of inherited cases of breast cancer.

That leaves a further 75 percent to 80 percent of such cases that must be due to other genes, for which Stratton and his colleagues have been searching. In 2002, the group - along with international collaborators - identified the CHEK2 gene as doubling a woman's risk of breast cancer when present in mutant form. The gene TP53 also is known to increase the risk of breast cancer when mutated, although mutations in it are very rare. (See BioWorld International, May 1, 2002.)

After a painstaking search, Stratton and colleagues now have identified the ATM gene as conferring a similar increase to CHEK2 in the risk of breast cancer.

About 0.5 percent of the UK population carry a single faulty copy of the ATM gene. When an individual inherits two copies of the mutant gene, the result is ataxia-telangiectasia. That disease is a progressive neurological affliction that causes severe disability in childhood, as well as blood cancers and respiratory problems.

It is the carriers of a single mutant copy of the gene who are at increased risk of breast cancer. That applies to about 400 of the 41,000 women who each year in the UK are diagnosed with breast cancer.

The Nature Genetics paper described how the research team compared 433 breast cancer patients with a family history of disease (but who did not have mutations in either BRCA1 or BRCA2) with 521 healthy women. Having sequenced the entire ATM gene, they found 12 faults in the patient group, compared with two in the healthy group.

Analysis showed that women who had inherited a mutant form of ATM had about double the population risk of developing breast cancer. Their risk of developing breast cancer by age 70 rose from one in 12 to one in six.

Stratton said: "In families with multiple cases of breast cancer due to BRCA1 or BRCA2, currently unaffected women can be screened for their family's mutation. Their predicted lifetime risk of breast cancer can either fall to 8 percent if they do not carry the mutation or rise to 70 percent if they do carry it. On the basis of those predicted risks, unaffected women are able to make more informed decisions about preventive options such as mammographic screening or prophylactic mastectomy. With ATM, the risk may rise to 15 percent if the mutant gene has been inherited. It will be important to do further research to find out the utility of mutation screening when this sort of figure is involved."

The main goal of Stratton and Rahman's group, however, is to identify all the genes involved in the inheritance of breast cancer. "Once we have found all of them, we can offer women in breast cancer families a large cocktail of genetic testing, and give these women a much more accurate view of what their risk really is," he said.

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