Defect Detector: Plugging holes in a breast cancer–gene screen

A European genetic test catches mutations that are missed by the sole test commercially available in the United States to screen the so-called breast cancer genes, a new study shows.

The genes, called BRCA1 and BRCA2, normally encode proteins that suppress rampant cell growth. But when these genes are mutated, they can yield defective proteins that leave a person vulnerable to cancer. A woman harboring a mutation in BRCA1, for example, faces a lifetime risk of 50 to 80 percent of developing breast cancer. A mutation in either BRCA gene also confers an increased risk of ovarian cancer.

Women with a known BRCA mutation can be closely monitored and frequently screened for breast cancer, or they may even choose to have their breasts or ovaries surgically removed to prevent disease.

In the United States, Myriad Genetics of Salt Lake City holds exclusive rights for testing for mutations in the BRCA genes. However, this exclusivity isn’t recognized in Canada or Europe. In recent years, European researchers have devised other BRCA tests and have reported BRCA mutations that the Myriad test doesn’t detect.

In the new study, geneticist Mary-Claire King of the University of Washington in Seattle and her colleagues identified 291 women with breast cancer, 6 women with ovarian cancer, and 3 men with breast cancer. Even though each had at least four relatives diagnosed with breast or ovarian cancer, the 300 participants tested negative for BRCA mutations by Myriad’s commercial test.

Using a Dutch test kit, King’s team analyzed each person’s BRCA genes. The scientists identified a BRCA mutation in 12 percent of the participants. The work appears in the March 22 Journal of the American Medical Association.

The two BRCA genes can harbor any of 1,000 or so different mutations, which alter the protein ultimately produced by the cell. Many of the mutations result from a change in DNA at a single position.

Myriad maintains that its screening test catches 99 percent of known mutations, but it can miss a defect that appears in only one of a person’s two copies of the gene. The alternative technique, called multiplex ligation-dependent probe amplification, catches such mutations, King says.

The commercial test wasn’t designed to ferret out every mutation hidden in a gene, says Gregory C. Critchfield, a pathologist and the president of Myriad. While the more exhaustive screen found what he considers “rare mutations,” Critchfield says that King’s team has produced “an important paper … that answers the [mutation] question for a subset of patients.”

The Myriad test “is not sufficient,” King concludes. “There are women who … are negative in normal genetic testing but who nonetheless carry cancer-causing mutations. They cannot be detected by methods used in this country. We need to have nonexclusive licensing for patents on genes.”