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Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer

Jochen Raedle, MD; Jörg Trojan, MD; Angela Brieger, PhD; Nicole Weber, BSc; Dieter Schäfer, MD; Guido Plotz, BSc; Elsbeth Staib-Sebler, MD; Susanne Kriener, MD; Mathias Lorenz, MD; and Stefan Zeuzem, MD
[+] Article and Author Information

From Johann Wolfgang Goethe-University, Frankfurt, Germany.


Copyright ©2004 by the American College of Physicians

Acknowledgments: The authors thank Ralf Lieberz for technical support and Hanns Ackermann and Eva Herrmann for statistical advice.

Grant Support: By research grant F 15/99 from the University of Frankfurt.

Requests for Single Reprints: Jochen Raedle, MD, Second Department of Internal Medicine, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany; e-mail, Raedle@em.uni-frankfurt.de.

Current Author Addresses: Drs. Raedle, Trojan, Brieger, and Zeuzem, Ms. Weber, and Mr. Plotz: Second Department of Internal Medicine, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.

Dr. Schäfer: Institute of Human Genetics, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.

Drs. Staib-Sebler and Lorenz: Department of General and Vascular Surgery, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.

Dr. Kriener: Department of Pathology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.

Author Contributions: Conception and design: J. Raedle, J. Trojan, A. Brieger, S. Zeuzem.

Analysis and interpretation of the data: J. Raedle, J. Trojan, A. Brieger, D. Schäfer.

Drafting of the article: J. Raedle, J. Trojan, D. Schäfer.

Critical revision of the article for important intellectual content: D. Schäfer, M. Lorenz, S. Zeuzem.

Final approval of the article: J. Raedle, J. Trojan, A. Brieger, N. Weber, D. Schäfer, G. Plotz, E. Staib-Sebler, S. Kriener, M. Lorenz, S. Zeuzem.

Provision of study materials or patients: J. Raedle, D. Schäfer, E. Staib-Sebler, S. Kriener, M. Lorenz, S. Zeuzem.

Statistical expertise: J. Raedle.

Obtaining of funding: J. Raedle.

Administrative, technical, or logistic support: N. Weber, S. Kriener, S. Zeuzem.

Collection and assembly of data: J. Raedle, J. Trojan, A. Brieger, N. Weber, G. Plotz, E. Staib-Sebler.


Ann Intern Med. 2001;135(8_Part_1):566-576. doi:10.7326/0003-4819-135-8_Part_1-200110160-00007
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Background: Microsatellite instability is a hallmark of mismatch repair deficiency in hereditary nonpolyposis colorectal cancer and results from mutations in the mismatch repair genes MLH1 or MSH2 or from gene inactivation associated with DNA methylation. The Bethesda guidelines were established to identify patients with colorectal cancer who should be tested for microsatellite instability.

Objective: To assess the Bethesda guidelines for detection of microsatellite instability and to determine the role of MLH1 promoter methylation in colorectal cancer.

Design: Prospective cohort study.

Setting: Tertiary care referral center in Frankfurt, Germany.

Patients: 125 consecutive patients with colorectal cancer.

Measurements: Patients were assessed according to the Bethesda guidelines, and tumor specimens were analyzed for microsatellite instability. Patients with microsatellite instability were tested for MLH1 promoter methylation and MLH1 and MSH2 germline mutations.

Results: Microsatellite instability was detected in 17 of 58 patients who fulfilled and 5 of 67 patients who did not fulfill criteria of the Bethesda guidelines. In 11 of 17 patients with microsatellite instability who fulfilled Bethesda guidelines, an MLH1 (n = 3), MSH2 (n = 7), or combined MLH1 and MSH2 (n = 1) mutation was found. Among the patients with microsatellite instability who did not fulfill Bethesda guidelines, no mutations were observed; MLH1 promoter methylation was observed in 6 of 11 patients with an MLH1 or MSH2 mutation and 5 of 11 patients without an MLH1 or MSH2 mutation.

Conclusions: The Bethesda guidelines are useful for selecting patients for microsatellite instability testing. MLH1 and MSH2 testing should be recommended in all patients with colorectal cancer and microsatellite instability who fulfill at least one Bethesda criterion. MLH1 promoter methylation may accompany rather than initiate carcinogenesis in patients with colorectal cancer who have mismatch repair gene defects.

Figures

Grahic Jump Location
Figure 1.
AllelicMLH1gene inactivation in colorectal cancer.Top.white circlesMLH1TCMiddle.MLH1Bottom.MLH1black circles

Normal allele with an unmethylated cytidine phosphate guanosine (CpG)-rich ( ) promoter region. The island is fully accessible to the transcription complex ( ) and does not interact with DNA methyl transferases. Mutations in the gene caused by somatic or germline alterations lead to expression of mutant MLH1 proteins. The promoter region is aberrantly methylated and transcriptionally silenced. The CpG sites are heavily methylated ( ) and fully accessible to DNA methyl transferases. The methylated CpG sites are interacting with complexes of methyl-cytosine–binding proteins and histone deacetylases, and the transcription complex is excluded from the region.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Strategy proposed for clinical and molecular assessment of patients with colorectal cancer.
Grahic Jump Location

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