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Genetic testing failed to detect all BRCA1 and BRCA2 mutations

Issue: April 1, 2006

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About 12% of patients with breast cancer and high familial risk of disease test negative for mutations in BRCA1 and BRCA2 genes when they, in fact, carry the cancer-associated mutations, according to a recent study.

“Conventional sequencing is not sufficient, as our study illustrated,” said senior researcher Mary-Claire King, PhD, from the University of Washington in Seattle, at a press briefing. It is critical to understand the implications of a negative test result, she said.

“The clinical dilemma is what to offer to women with a high probability of carrying a mutation in BRCA1 or BRCA2 but with negative commercial test results,” King said.

Inherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancers. Clinical options for women at high genetic risk for breast cancer include screening starting at a young age, the use of highly sensitive detection methods and prophylactic surgeries of the ovaries or breast. Because prophylactic surgeries, while highly effective in reducing risk, are also highly invasive, it is particularly important to distinguish mutation carriers from noncarriers with similarly severe family histories. Women with BRCA1 or BRCA2 mutations are possible candidates for such surgeries.

Between 2002 and 2005, King and colleagues evaluated DNA and RNA samples from 300 breast cancer probands and used multiple screening approaches to identify mutations of all genomic classes in BRCA1, BRCA2, CHEK2, TP53 and PTEN.

Of the 300 probands, 17% carried previously undetected mutations, including 12% with genomic rearrangements of

BRCA1 or BRCA2, 5% with CHEK2 mutations and 1% with TP53 mutations.

“Our results suggest that genetic testing, as currently carried out in the United States, does not provide all available information to women at risk,” King said.

For more information:

• Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295:1379-1388.