Hereditary nonpolyposis colorectal cancer (HNPCC), also named Lynch syndrome, is a genetic disorder that accounts for approximately 1 percent to 3 percent of all colorectal cancers, according to background information in the article. HNPCC is caused by mutations in genes, mainly MSH2 and MLH1. In HNPCC, colorectal tumors have a DNA abnormality called microsatellite instability. Although a great advance in the understanding of the molecular basis of HNPCC has taken place in the last decade, optimal selection of individuals for HNPCC genetic testing remains challenging.
Virginia Pinol, M.D., of the University of Barcelona, Spain, and colleagues conducted a study to determine the most effective and efficient way to detect MSH2 or MLH1 gene carriers in patients with newly diagnosed colorectal cancers. The study included 1,222 patients from 20 hospitals in Spain with newly diagnosed colorectal cancer between November 1, 2000 and October 31, 2001. Patients underwent microsatellite instability testing and MSH2/MLH1 immunostaining (laboratory technique used to determine properties of tissue). Patients whose tumors exhibited microsatellite instability and/or lack of protein expression underwent MSH2/MLH1 germline (cells that have genetic material that may be passed to a child) testing.
Two hundred eighty-seven patients (23.5 percent) fulfilled the revised Bethesda guidelines. Ninety-one patients (7.4 percent) had a mismatch repair deficiency. The researchers found that strategies based on either microsatellite instability testing or immunostaining patients according to the revised Bethesda guidelines were the most effective (sensitivity, 81.8 percent and 81.8 percent; specificity, 98.0 percent and 98.2 percent; positive predictive value, 27.3 percent and 29.0 percent, respectively) to identify MSH2/MLH1 gene carriers. Further analysis confirmed the revised Bethesda guidelines as the most discriminating set of clinical parameters.
"In conclusion, our results demonstrate that the revised Bethesda guidelines constitute a very useful approach to select patients at risk for HNPCC. In patients fulfilling these criteria, both microsatellite instability testing and protein immunostaining are equivalent and highly cost-effective strategies to further select those patients who should be tested for MSH2/MLH1 germline mutations. Considering this equivalence and that immunostaining is more available than DNA analysis in a clincial setting, the use of immunohistochemistry [a test that shows specific antigens in tissues] may help identify a larger proportion of patients with HNPCC," the authors write.
(JAMA. 2005;293:1986-1994. Available post-embargo at JAMA.com)
Editor's Note: Please see the JAMA article for funding/support information.
Editorial: Progress in Genetic Testing, Classification, and Identification of Lynch Syndrome
In an accompanying editorial, Hans F. A. Vasen, M.D., of Leiden University Medical Center, the Netherlands, and C. Richard Boland, M.D., of Baylor University Medical Center, Dallas, discuss the findings of Pinol et al.
"In patients who meet the Bethesda guidelines, the first step might be MSI [microsatellite instability] analysis followed by immunohistochemical analysis of all tumors classified as MSI-high. Even though MSI and immunohistochemical analyses have been available for several years, they are being applied on a relatively small scale at this time. Therefore, efforts should be undertaken to make these molecular diagnostics tools available for all clinicians. Finally, to make optimal use of them, clinicians should be familiar with the Bethesda guidelines to know in which patients the tests should be performed," they write.
(JAMA. 2005;293:2028-2029. Available post-embargo at JAMA.com)
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