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Hunting for BRCA3

An international team of scientists is homing in on the site of a third gene that may be involved in the onset of hereditary breast cancer. If the gene is found, the work will pave the way to improved genetic counseling and cancer detection and treatment for members of families with a history of breast cancer.

Defects in so-called "susceptibility genes" contribute to the development of 5% to 10% of all breast cancers, greatly increasing a woman's risk of getting the disease. To date, researchers have identified two breast cancer susceptibility genes, called BRCA1 and BRCA2, but flaws in these genes probably account for no more than one-third of all hereditary breast cancers.

To track down other susceptibility genes, research teams from Finland, Sweden, Iceland, and the United States joined forces. They identified 37 families who are afflicted with high rates of breast cancer but who do not carry known BRCA1 or BRCA2 mutations. By using a technique called comparative genomic hybridization on DNA from tumor and normal tissue from 61 women, the researchers discovered five likely regions for breast cancer genes. To narrow their search, the teams sifted through these regions using two new mathematical models. Finally, they drew on the well-established methods of genotyping and linkage analysis to identify stretches of similar DNA shared by breast cancer patients in a family.

Combined, these techniques yielded a region on chromosome 13 as the likely site of a third susceptibility gene, the teams report in the 15 August Proceedings of the National Academy of Sciences. Although it may take months to years to pinpoint the gene at fault, this work is "an important intermediate step in narrowing the search," says team member Olli Kallioniemi, a cancer geneticist at the National Human Genome Research Institute in Bethesda, Maryland.

Other scientists are greeting the announcement guardedly, however. Population geneticist Mark Skolnick, chief scientific officer for Myriad Genetics Inc. in Salt Lake City, who led the team that identified BRCA1, finds the work "potentially very significant," but cautions that the statistical evidence is not conclusive.

Mary-Claire King, a geneticist at the University of Washington, Seattle, who pioneered the search for breast cancer susceptibility genes, praises the teams' integrative approach. But she and Skolnick both note that BRCA2 also resides on chromosome 13. It's possible, they note, that undiscovered defects around this gene may have confounded the analysis. Definitive proof that the team has in fact found a new breast cancer susceptibility gene, they say, won't come until the researchers replicate their work in other family groups or find the gene itself.

Related sites
The NCI's information page on breast cancer (CancerNET)