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Detecting mutations
Current gene tests not enough, according to recent study
  
By Julie Buckles

Sometimes one test isn't enough when it comes to detecting hereditary breast and ovarian cancer, according to findings published in the September issue of the American Journal of Human Genetics. Researchers recently uncovered genetic mutations, previously missed by standard gene tests, in the breast cancer gene BRCA1, adding to a growing body of evidence that says current screening methods are not enough.

The BRCA1 and BRCA2 genes account for from 85 to 100 percent of hereditary breast and ovarian breast cancer cases, which are only a small proportion of the total incidence of breast cancer cases overall. Previous studies show that standard tests known as PCR-based mutation-detection tests do not reveal enough mutations to match these numbers. "There is a discrepancy between what we expect and what we see from test results," says Meredith A. Unger, of the University of Pennsylvania School of Medicine.

Unger and colleagues screened 106 families diagnosed with hereditary breast and ovarian cancer using PCR-based mutation-detection tests. Of those, 42 families tested negative, even though there was a high likelihood the mutations existed. Researchers next tested the 42 families using an older and more labor-intensive method called Southern blot analysis and uncovered mutations in five families, or 12 percent, that were missed by the PCR-based tests.


Hereditary forms of cancer account for five to ten percent of all breast and ovarian cancer cases.

The problem, says Unger, is that PCR-based testing searches for smaller base-pair mutations in the coding region of genes and can miss so-called genomic rearrangements. Through Southern blot analysis, they discovered large mutations, all of which were genomic rearrangements. Researchers don't advocate using Southern blot analysis on a larger scale—it's too time-consuming—but rather want to develop a better second test for families who are at high risk and have tested negative using standard gene tests. The BRCA1 and BRCA2 genes are most common in women of Ashkenazi jewish descent.

Of course, mutations in 37 families remain missing. The next phase is to develop techniques to root them out, Unger says. Hereditary forms of cancer account for five to 10 percent of all breast and ovarian cancer cases. As commercial testing becomes more routine in medical practice, Unger says, "genomic rearrangements need to be carefully considered as a cause of false-negative results, following PCR-based analysis."

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Unger, M. A. et al. Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Gen 67, 841-850 (2000).
 

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