Women at highest risk for cancer may be falsely reassured

About 12% of women who test for inherited mutations of BRCA1 and BRCA2 receive a false-negative result, according to the findings of a recent study. In addition, about one in 20 with mutations in CHEK2 and TP53, two additional genes that have been found to increase the risk of breast cancer, are also falsely reassured.

That's because the only commercially available test in the US, BRACAnalysis (Myriad Genetics, Inc., Salt Lake City, Utah) doesn't detect all the possible mutations that can occur. The assay sequences DNA looking for only five rearrangements in the key genes.

To determine the rate of false-negative results, researchers sampled DNA from 300 women belonging to families in which four or more members were diagnosed with breast or ovarian cancer and who received a negative result with BRACAnalysis. The researchers then searched the DNA with six different methods, including multiplex ligation-dependent probe amplification, which is relatively inexpensive, widely used throughout Europe, and which indicates the presence of any rearrangement. They determined that about 12% of women with mutations in the key BRCA genes are being missed.

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.

Commentary by Victoria Green, MD, MBA, JD, Associate Professor, Department of Gynecology and Obstetrics, Emory University, Atlanta, Ga.:

"The results of this study illustrate the importance of counseling surrounding testing for inherited breast cancer susceptibility. Patients with significant histories may still require increased surveillance despite negative testing as large rearrangements and possibly promoter region mutations may be missed with current methods. Patients should be made aware that current testing methods may not detect many of these changes as well as uncommon mutations and thus they may still be at risk. On a related note, the ethics of test patents have been questioned extensively. Although the company that markets commercial BRCA testing continuously monitors and develops enhancements, the lack of competition may cause one to fear slowed responses and impede widespread advancement in knowledge."