Mutation location may predict cancer type.

Some mutations stop genes cold, preventing them from producing proteins; others force genes to create abbreviated or misshapen molecules that function incorrectly. Consequently, different mutations in the same gene can lead to radically disparate outcomes.

Researchers now have evidence that the site of mutations in the BRCA1 gene, which are responsible for most familial cases of ovarian and breast cancer, may partially determine whether an individual will suffer a particular type of cancer. A new statistical analysis of 32 British families with BRCA1 mutations suggests that when the genetic flaw occurs in one portion of the gene, family members face a lower chance of developing ovarian cancer than when it occurs elsewhere.

If confirmed, the finding may illuminate the roles of BRCA1's protein in breast and ovarian cells and enable physicians to inform patients more accurately of their cancer risks.

"It would be of great clinical importance if this result could be supported by a lot more data," says Simon A. Gayther of the Cancer Research Campaign in Cambridge, England. Gayther and his colleagues discuss their work in the December Nature Genetics.

Cloned about a year ago, BRCA1 has quickly become one of the most thoroughly studied genes of all time. In February, for example, a large group of researchers reported on an extensive survey of BRCA1 mutations in women with breast or ovarian cancer (SN: 2/25/95, p.119). Though the result was not statistically significant, says Gayther, the survey "hinted" that the site of BRCA1's mutation might make a difference in cancer type.

In their study, Gayther and his coworkers found 22 different mutations in BRCA1, including 14 not previously identified. When the investigators considered the mutations' locations in relation to the cancers affecting each family, they found a statistically significant correlation. Mutations in the final third of the gene appeared less likely to create ovarian cancer than were mutations in other areas of BRCA1. The mutation's site did not seem to change breast cancer risk.

The variation in outcomes of BRCA1 mutations may reflect the different duties the gene's protein performs in breast and ovarian cells, the researchers suggest. The importance of a mutation's position within the gene isn't unprecedented in cancer research, notes Gayther. The aggressiveness of colon cancer depends on where the APC gene is mutated, he says.

Gayther and other breast cancer researchers caution that further studies in more diverse populations must be done to solidify the BRCA1 finding. Perhaps, says Gayther, the mutation's position may become important only in the context of a particular lifestyle or a particular genetic background.

In fact, Steven Narod of the University of Toronto says that his unpublished research and that of others do not support the idea that the site of BRCA1's mutation significantly changes the risk of either cancer. "I don't think the differences are very strong," asserts Narod. "I don't expect it will change the way we practice medicine."