Selecting Patients with Colorectal Cancer To Test for Genetic Abnormalities

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The summary below is from the full report titled "Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer." It is in the 16 October 2001 issue of Annals of Internal Medicine (volume 135, pages 566-576). The authors are J Raedle, J Trojan, A Brieger, N Weber, D Schäfer, G Plotz, E Staib-Sebler, S Kriener, M Lorenz, and S Zeuzem.

What is the problem and what is known about it so far?

Colorectal cancer affects the colon (large intestine) or rectum. An inherited cancer syndrome called hereditary nonpolyposis colorectal cancer (HNPCC) is the cause of colorectal cancer in some patients. People with HNPCC have a higher than usual risk for colorectal and several other types of cancer. In HNPCC, colorectal tumors have a DNA abnormality (DNA is the substance that makes up genes) called microsatellite instability. In addition, people with HNPCC frequently have abnormalities (mutations) in two genes known as MLH1 and MSH2. Patients with an MLH1 or MSH2 mutation are more likely to have colorectal tumors with microsatellite instability than are patients without these mutations. Identifying patients with an MLH1 or MSH2 mutation may be important so that they and their family members can be monitored closely for the development of colorectal tumors. The Bethesda guidelines identify conditions that suggest that a patient mi t have HNPCC (for example, colorectal cancer in two successive generations or cancer at a young age). However, many people who meet a Bethesda criterion do not have HNPCC. It would be useful to have a way to identify people with colorectal cancer who should undergo genetic testing for mutations in MLH1 and MSH2.

Why did the researchers do this particular study?

To find out whether combining the Bethesda criteria with tests for microsatellite instability can help identify people with HNPCC mutations in the MLH1 and MSH2 genes.

Who was studied?

125 patients with colorectal cancer at a university hospital in Germany.

How was the study done?

The researchers classified the study patients as meeting or not meeting Bethesda criteria and then tested all patients for microsatellite instability. Patients with microsatellite instability were then tested for MLH1 and MSH2 mutations.

What did the researchers find?

Of the 58 patients who met Bethesda criteria, 17 had microsatellite instability compared with only 5 of the 67 patients who did not meet any Bethesda criterion. Eleven of the 17 patients with microsatellite instability who met Bethesda criteria had at least one of the HNPCC mutations compared with no mutations in the patients with microsatellite instability who did not meet any Bethesda criterion.

What were the limitations of the study?

The number of patients with an HNPCC mutation was small; therefore, the accuracy of the Bethesda criteria combined with microsatellite instability is uncertain. This study does not tell us whether genetic testing actually helped patients or their family members.

What are the implications of the study?

Patients with colorectal cancer who meet Bethesda criteria and have microsatellite instability are more likely to have HNPCC mutations than patients who do not. Patients who do not meet Bethesda criteria and have microsatellite instability are unlikely to have these mutations. Patients who meet at least one Bethesda criterion and have a tumor that shows microsatellite instability should undergo testing for MLH1 and MSH2 mutations.