Search for more familial breast ca genes heats up. (80% of Risk Still Unexplained).

SAN ANTONIO -- The BRCA1 and 2 mutations together account for only 15%-20% of the excess familial risk of breast cancer, Dr. Bruce Ponder said at the annual breast cancer symposium sponsored by the San Antonio Cancer Institute.

An intensive search is underway for the genetic mutations responsible for the remaining 80% or more of this excess familial risk. There are two possibilities. The culprits might consist of a few genes with potent mutations that place a relatively small number of people at very high risk. Such mutations, provided that they exist, would be akin to BRCA3, 4, 5, and so forth.

The other possibility--and the one Dr. Ponder is betting on in his own research--is that the excess risk is due to the combined small genetic variants. A weakly predisposing allele that confers a mere twofold increased breast cancer risk but has a frequency of 20% could account for up to 20% of all breast cancers occurring by age 70--a far greater effect than mutations in BRAC1 and 2, which confer great risk to affected individuals but are uncommon.

"It's like faces. They are the result of the combined effect of a lot of different genes. If genes can give people different faces, might they not also confer different risk for breast cancer?" asked Dr. Ponder, who is professor of oncology at the University of Cambridge in England.

The hypothesis he is pursuing is that while normal variations in each of the relevant genes would individually have a weak effect on breast cancer risk, collectively such genes--which might number 100 or more--would define the "face" of familial breast cancer. It might then be possible to construct individual genetic profiles for breast cancer risk that could have a major public health impact by allowing far more precisely targeted use of screening and intervention resources.

The widely used Gail model of ...