Testing misses some breast cancer mutations

Commercial genetic testing does not detect all of the cancer-associated inherited mutations in women with an extensive family history of breast or ovarian cancer, according to a study in the Journal of the American Medical Association.

"Women who were familial breast cancer patients were being commercially tested for inherited mutations in BRCA1 and BRCA2, and a very large number had reports returned that said they had negative results," Dr. Mary-Claire King said in a presentation Tuesday at a press briefing coinciding with publication of the Journal's theme issue devoted to women's health.

King noted that it has been clear since BRCA1 mutations were first reported "that there were mutations that in principle could not be detected by conventional sequencing methods, no matter how perfectly they were carried out."

In the US, nearly all genetic testing of BRCA1 and BRCA2 is conducted by one company. Most of the mutations it can detect are small deletions or duplications.

King, from the University of Washington in Seattle, and her research team set out to find if any mutations are missed by commercial tests. That's important, she added, because "risk reduction interventions for those with mutations are highly effective, but they are also horrifically invasive, including (preventative ovarian surgery) and mastectomy that one would not undertake unless she was at extremely high risk."

The study included 300 patients with breast or ovarian cancer and at least three affected family members, for whom commercial testing yielded negative results.

The researchers used DNA probe amplification, and other DNA- and RNA-based methods to detect rearrangements in BRCA1 and BRCA2 genes, as well as other gene mutations in CHEK2, TP53, and PTEN.

They found that 35 (12 percent) of the women had gene rearrangements of BRCA1 or BRCA2. The reason they couldn't be detected by the commercial method, King explained, was that the gene deletions or duplications were much larger than conventional gene sequencing can detect.

Another 14 (5 percent) had mutations in CHEK2, which confers a two-fold risk of breast cancer but no elevation in risk of ovarian cancer. Three women (1 percent) had TP53 mutations, which confers a 90-percent risk of developing one of the cancers associated with the Li-Fraumeni syndrome, a rare genetic disease that increases the rate of various tumor types and mainly affects young people.

All the mutations they found were individually rare, the researcher noted.

Many of the other subjects may also be carrying cancer mutation genes that have not yet been recognized, King told Reuters Health. "We are continuing to look for additional breast cancer genes that will explain inherited breast cancer in those patients."

Meanwhile, a partial solution to improve screening, she added, would be "an open, competitive marketplace for development of genetic testing for BRCA1 and BRCA2, just as we have for most other genes."