Breast cancer gene hides many mutants.

On Oct. 7, a team of 45 researchers published a paper describing a gene responsible for some cases of inherited breast cancer. Immediately, thereafter, gene hunters all over North America began the race to confirm the finding.

Now, three scientific teams have done just that. Their results verify the link between the gene BRCA1 and breast or ovarian cancer, or both, in some families. Taken together, the data on 100 families provide a sobering view of the complexity of these cancers.

Collectively, the groups found not one, not two, but 22 distinct defects in the genetic coding that makes up BRCA1. "There's a lot of heterogeneity of mutations in this gene," says Francis S. Collins, director of the National Center for Human Genome Research in Bethesda, Md., and leader of one of the research teams.

In the short run, those results dash the hope of devising a simple blood test to identify people who have inherited a mutant BRCA1. The three scientific reports, as well as an editorial, appear in the December NATURE GENETICS.

In one report, Collins and his colleagues studied 50 families with a history of breast and ovarian cancer. The researchers obtained sample DNA from each individual in the study, homed in on BRCA1, and scoured the gene for flaws in the genetic code. They found a number of mutations, one of which contains a clue to BRCA1's function. In some cases, BRCA1 has a flaw that can lead to the production of a defective protein, one with an altered zinc-finger region.

Researchers believe that BRCA1, when healthy, may act as a tumor-suppressor gene. The triad of reports suggests that a mutant BRCA1 produces a flawed protein or no protein at all. Researchers suspect that the BRCA1 protein product helps regulate other genes in a cell. When it's absent or malfunctioning, a cell may turn malignant.

The team led by Mary-Claire King of the University of California, Berkeley, found a mutation that causes a similar mistake in the zinc-finger region of the BRCA1 protein. This study of 20 families also describes a handful of BRCA1 mutations. One notable one: a defect in BRCA1 that seems to predispose women to develop breast cancer at a very early age.

Finally, Steven A. Narod of McGill University in Montreal and his coworkers analyzed BRCA1 in 30 Canadian families. This team also found a number of flaws in the gene.

When considered together, the results from the three studies show that just 31 of the 100 families showed a BRCA1 mutation. What about the remaining 69 families, all of which had a history of breast and ovarian cancer? The DNA probe could have missed some BRCA1 defects.

"It's still possible there are unaccounted-for mutations," says Lawrence C. Brody of the National Center for Human Genome Research. Then again, some families' tumors may be sporadic and thus have no common genetic basis, points out Brody, coauthor of one report.

These papers indicate that no predominant BRCA1 mutation exists, and they suggest that the "prospects for wide-scale screening of BRCA1 look dim," says NATURE GENETICS Editor Kevin Davies. If further study bears that suspicion out, a blood test for mutations in BRCA1 would have to look for a great number of flaws in the genetic code, he adds.