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New Mutations Too Big for BRCA1 Tests

Dutch researchers have identified several new mutations in a gene that predisposes some women to breast cancer. The alterations in the BRCA1 gene, described in the November issue of Nature Genetics, could account for up to a third of BRCA1-related breast cancer cases in some European populations. The impact for American women is probably smaller, experts say, because tests already catch 90% of BRCA1 mutations in the U.S. population.

Commercial tests scan samples of a patient's blood for BRCA1 mutations that are linked to breast cancer. Such tests, however, have mysteriously failed to flag mutations in 20% to 30% of European women with a family history of breast cancer, even when their cancer could be linked to BRCA1 by damage to chromosome 17, BRCA1's home. A clue emerged last year when researchers discovered that BRCA1 has an above-average number of fragile stretches of DNA called "Alu repeats," which would make the gene susceptible to losing large chunks of DNA. These hotspots might be prone to large deletions that commercial tests might miss.

To test this theory, Peter Devilee of the Leiden University Medical Center in the Netherlands and his colleagues examined the genes of 220 Dutch women. Thirty-three had hints of BRCA1 trouble--chromosomal damage and family history of breast cancer--but had tested negative for known mutations. The team employed a technique called Southern blotting to examine fragments of the BRCA1 gene that are much larger than the tiny snippets scanned by the polymerase chain reaction (PCR) in commercial tests. Twelve of the women, they found, were missing big chunks of BRCA1. The findings jibe with previous reports that PCR tests sometimes overlook a gene with large deletions, detecting only the other, normal copy of the gene.

Experts say the findings should lead to improved BRCA1 tests in the Netherlands and other European countries. The large deletions could also help provide answers for American women at risk of BRCA1-related cancer as well, although many genetic populations in the United States differ greatly from those in Europe. Experts have estimated that such deletions may account for 10% of all BRCA1 mutations in the U.S. population, says human geneticist Brian Ward, vice president of laboratory operations at Myriad Genetics, one of the main producers of commercial BRCA1 tests.

Other experts welcome the Dutch result for a second reason as well: It could lead to insights into mechanisms behind noninherited breast cancer. Cancer geneticist Mary-Claire King of the University of Washington argues that BRCA1's susceptibility to large deletions and genetic rearrangements could lead to sporadic tumors. The new result, she says, "will encourage people to look at tumors where it's very likely that this phenomenon is even more common."