Share this article on:

Genetic Testing Plus Bethesda Guidelines Help Screen for Lynch Syndrome

Fuerst, Mark L.

doi: 10.1097/01.COT.0000294682.41348.39

Combined use of immunohistochemistry and the revised Bethesda guidelines to identify people with hereditary nonpolyposis colorectal cancer (HNPCC) may select out those from the general population who should undergo genetic testing for the cancer, according to a new study.

While great advances have been made in understanding the molecular basis of HNPCC, also known as the Lynch syndrome, optimal selection of people for genetic testing remains challenging. The study, by the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association and published this spring in the Journal of the American Medical Association (2005; 293:1986–1994), was done to establish the most efficient strategy to detect the carriers of germ-line mutations in the DNA mismatch repair genes MSH2 and MLH1, the main causes of HNPCC.

Defects in this pathway led to changes in the length of nucleotide repeat sequences of tumor DNA—i.e., microsatellite instability.

The prospective, multicenter, nationwide study in 20 hospitals of 1,222 patients with newly diagnosed colorectal cancer included microsatellite instability testing and MSH2/MLH1 immunostaining in all patients. Those whose tumors exhibited microsatellite instability and/or lack of protein expression underwent MSH2/MLH1 germ-line testing.

Both the effectiveness and efficiency of microsatellite instability testing and immunostaining were evaluated with respect to the presence of MSH2/MLH1 germ-line mutations.

Some 287 patients (23.5%) fulfilled the revised Bethesda guidelines, and 91 patients (7.4%) had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (83 patients) or loss of protein expression (81 patients).

Germ-line testing identified 11 mutations in the genes of either MSH2 (7 patients) or MLH1 (4 patients).

Back to Top | Article Outline

Most Effective Way to Identify MSH2/MLH1 Gene Carriers

The most effective way to identify MSH2/MLH1 gene carriers was through strategies based on either microsatellite instability testing or immunostaining selection of patients according to the revised Bethesda guidelines, with a sensitivity of 81.8% for both methods, and a specificity of 98.0% and 98.2%, respectively.



A logistic regression analysis confirmed the revised Bethesda guidelines as the most discriminating set of clinical parameters.

Another study of 1,066 HNPCC patients in Ohio by researchers at Ohio State University also found that the effectiveness of immunohistochemical screening was similar to that of microsatellite instability genotyping in identifying mutations among patients and their family members (N Engl J Med 2005;352:1851–1860).

One of the Spanish researchers, Antoni Castells, MD, from the Department of Gastroenterology at Hospital Clinic Villarroel in Barcelona, pointed to two important findings from the study: First, immunohistochemistry for mismatch repair proteins is equivalent to microsatellite testing as a screening method for the identification of colorectal cancer patients who should undergo genetic testing. Second, the revised Bethesda guidelines are useful for the identification of HNPCC patients.

“Considering this equivalence and the fact that immunostaining is more available than DNA analysis in a clinical setting, the use of immunohistochemistry may contribute to identify a larger proportion of patients with HNPCC,” Dr. Castells said.

Currently, identification of HNPCC patients is mainly performed among high-risk populations. “Our results suggest that a combination of the revised Bethesda guidelines and immunohistochemistry makes feasible the selection of patients who should undergo genetic testing in the general population.”

He pointed out that a small percentage of HNPCC cases (about 5% to 7%) are related to the presence of germ-line mutations in another mismatch repair gene, the MSH6 gene, but that in the study that he and his colleagues conducted, neither immunohistochemistry for MSH6 nor genetic testing for the gene was performed.

He recommended that practicing oncologists become familiar with the revised Bethesda guidelines and “try to push their pathologists to implement MSH2/MLH1 (and eventually MSH6) immunohistochemistry for the routine evaluation of colorectal cancer samples.”

Henry T. Lynch, MD, Professor of Medicine and Professor and Chairman of Preventive Medicine and Public Health at Creighton University, who was the first to describe the hereditary colon cancer syndrome, said that to be both more effective and more cost-effective, testing should be restricted to only those at high risk.

“This would not only be economical but would spare the emotional stress that could affect people with false-positive findings,” he said. “The value of testing with immunohistochemistry staining and microsatellite instability is high, but I don't think it prudent until we get more evidence.”

Dr. Lynch also noted that only a limited number of centers are currently engaged in such testing.



At that point, the clinician will be in a better position to make a risk estimate based on microsatellite instability and immunohistochemistry, he said.

Dr. Lynch also pointed out that clinicians have to test other relatives: “If you do all of your work on a single patient and ignore other family members, you are providing a limited service to the family.”

© 2005 Lippincott Williams & Wilkins, Inc.
Home  Clinical Resource Center
Current Issue       Search OT
Archives Get OT Enews
Blogs Email us!