The work, published in the September 21, 2005, issue of the Journal of the National Cancer Institute, is one of the first prospective studies to allow doctors to tailor ovarian cancer screening recommendations for women with a family history of breast cancer but with no identifiable BRCA mutation.

In the ten years since the discovery of BRCA1 and BRCA2 genes, it has been learned that the risk for ovarian cancer in families with mutations in these genes is increased 6- to 61-fold. However, it has also emerged that up to half of families with multiple cases of breast cancer do not have mutations in either BRCA1 or BRCA2. Up until the current study, there has been limited data with which to inform such families as to their risk for ovarian cancer.

The MSKCC Clinical Genetics Service studied 199 families with multiple cases of breast cancer but no identified BRCA mutation. During follow-up, 19 new cases of breast cancer were diagnosed “ three times more than the six cases that were expected. Only one case of ovarian cancer was diagnosed, which is what researchers would have anticipated in an average risk population.

While the authors conclude that women from these families do not have an increased risk of ovarian cancer, they also indicate that the genetic mechanism for up to half of hereditary breast cancer remains unknown. Ongoing research at MSKCC, in collaboration with other scientists in the US, Canada, and Israel, is underway to map undiscovered genes associated with hereditary breast cancer.

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The group used a lactamase gene from the Bacillus cereus soil bacteria and tested it in the laboratory strain E. coli. The gene is very similar to lactamase genes found in disease-causing bacteria such as Pseudomonas and Acinetobacter -- common culprits in resistant, hard-to-treat hospital infections. And it is almost identical to a lactamase gene found in Bacillus anthracis, which causes anthrax.

Together, the four mutations identified by the group increased the enzyme's efficiency at inactivating cephalexin seven-fold. The mutations influenced the enzyme's active site, where the chopping of antibiotic molecules takes place. One of the mutations has already been found in nature, in a lactamase from Pseudomonas.

In some cases, there is a tradeoff associated with antibiotic resistance: the bacteria's success in fighting a particular antibiotic can cause it to lose efficiency in inactivating other antibiotics. But that was not the case here.

"This evolved enzyme works better against cephalexin and with the same efficiency on other antibiotics, as well," said Vila. In fact, the mutant enzyme inactivated seven other cephalosporins as efficiently as or better than the original enzyme. "So it hasn't lost anything, and the outcome is that the bacteria has increased its range of resistance. This is a huge concern in the clinic."

To date, there are no known inhibitors of metallo- -lactamases, but directed evolution could help in their design, Vila said, by giving drug makers a reliable prediction of what the next generation of enzymes will look like. "Since we were able to reproduce the natural evolution in the test tube, you could generate a more efficient lactamase to use as a target, so that your inhibitor would be one step ahead."

This would give science an edge in the resistance race, and it might help slow the vicious cycle enough to develop antibiotics impervious to lactamases.

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