Testing misses some breast cancer-related mutations

An article appearing in newspapers around the world refers to a recent study published this week in the Journal of the American Medical Association (JAMA 2006;295:1379-1388). The following is a direct quote of the version written for Reuters Health, by Karla Gale:  
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Commercial genetic testing does not detect all cancer-associated inherited mutations in women with a severe family history of breast or ovarian cancer. . .

"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 for March 22/29 devoted to women's health.

Dr. 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 carried out by one company. Most of the mutations it can detect are small deletions or duplications.

Dr. King, from the University of Washington in Seattle, and her research team set out to quantify how many mutations would be 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 prophylactic salpingo-oophorectomy and mastectomy that one would not undertake unless she was at extremely high risk."

Their 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 multiplex ligation-dependent probe amplification [MLPA], and other DNA- and RNA-based methods to detect genomic rearrangements in BRCA1 and BRCA2 as well as germline mutations in CHEK2, TP53, and PTEN.

They found that 35 (12%) of subjects had genomic rearrangements of BRCA1 or BRCA2. The reason they couldn't be detected by the commercial method, Dr. King explained, is that "they were genomic deletions or duplications that are much larger than can be detected by conventional sequencing, ranging from 1000 to 170,000 base pairs, incorporating part of BRCA1 or BRCA2."

Another 14 (5%) had mutations in CHEK2, which confers a doubled risk of breast cancer but no elevation in risk of ovarian cancer. Three (1%) had TP53 mutations, which confer a 90% risk of developing one of the cancers associated with the Li-Fraumeni syndrome.

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, Dr. 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 improving genetic testing, 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."

That includes "nonexclusive licensing of patents on genes, because competition is the best way to improve technology and bring the price down." As opposed to drugs for which patents make sense, she added, genetic tests are much cheaper and take less time to develop, and they are not subject to FDA approval.

Breast cancer can be expected to hit one woman in eight during her lifetime. Testing promoted as a predictor for breast cancer, and controlled primarily by one company, only looks for mutations in BRCA1 and BRCA2, and these genes are associated with only 5% of breast cancers. Now, we also know that there are mutations that are not being detected even by this test. So, genetic testing even for breast cancer--the most widely touted of tests available for potential disease--has a long way to go.

Marie Godfrey, PhD

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