Genetic Testing Misses Some Breast Cancer Gene Mutations

Mary-Claire King, Ph.D.
University of Washington
R01ES013160

Background: In 1994, NIEHS researchers discovered the first breast cancer gene and named in BRCA1. Shortly after that, BRCA2 was discovered and since then other breast cancer genes have been discovered. As predicted in 1994, the discovery of the BRCA1 gene has had major implications for public health, including the potential for early tumor detection and improved prognosis. Women who are at risk for familial breast or ovarian cancer are routinely tested for mutations in BRCA1 and BRCA2. However, new research, also by an NIEHS-supported scientist, has discovered that current commercial testing fails to detect a significant number of mutations.

Advance: From 2002-2005, Dr. Mary-Claire King of the University of Washington conducted DNA- and RNA-based tests to detect genomic rearrangements in BRCA1 and BRCA2 and germ-line mutations in CHEK2, TP53, and PTEN in subjects from over 300 U.S. families with 4 or more cases of breast or ovarian cancer. These cases had been commercially tested and found negative for BRCA1 and BRCA2 mutations. Of the 300 subjects, 17% were found to have previously undetected mutations. Thirty-five had rearrangements of BRCA1 and BRCA2, 14 had CHEK2 mutations, and 3 had TP53 mutations.

Implications: This study demonstrates that commercial genetic testing does not detect all mutations in women with a strong familial history of breast and ovarian cancer. According to Dr. King, these findings are important because "risk reduction interventions for those with mutations are highly effective." The results suggest that commercial testing should be expanded to include these and possibly other mutations so that at-risk women have the best information available when deciding to undergo invasive interventions such as preventive mastectomy or ovary removal.

Citation: Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006 Mar 22;295(12):1379-88.