Limitations in Detecting Cancer

Mary-Claire King, Ph.D., of the University of Washington, Seattle and colleagues conducted a study to determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families with negative results from commercial genetic testing of BRCA1 and BRCA2. Between 2002-2005, the researchers evaluated DNA and RNA samples from 300 breast cancer probands and used multiple different screening approaches to identify mutations of all genomic classes in BRCA1, BRCA2, CHEK2, TP53, and PTEN.

The researchers found that of the 300 probands, 52 (17 percent) carried previously undetected mutations, including 35 (12 percent) with genomic rearrangements of BRCA1 or BRCA2, 14 (5 percent) with CHEK2 mutations, and 3 (1 percent) with TP53 mutations. No inherited mutations were detected in PTEN. At BRCA1 and BRCA2, 22 different genomic rearrangements were found. Of these, 14 were not previously described and all were individually rare. Inherited rearrangements of BRCA1 were more frequent among probands diagnosed when younger than 40 years (16 percent) than among probands diagnosed when 40 years or older (6.5 percent).

"Our results suggest that genetic testing, as currently carried out in the United States, does not provide all available information to women at risk. Our data indicate that 12 percent of those from high-risk families with breast cancer and with negative commercial genetic test results for BRCA1 and BRCA2 nonetheless carry cancer-predisposing genomic deletions or duplications in one of these genes," the authors write.; Source: JAMA and Archives Journals