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Diagnostic Microsatellite Instability: Definition and Correlation with Mismatch Repair Protein Expression¹

Institute of Pathology [W. D., S. W., J. R.] and Department of Internal Medicine I [F. K.], University of Regensburg, Franz-Josef-Strauss-Allee, D-93042 Regensburg, Germany, and Department of Microbiology and Immunology, Genetics and Molecular Biology Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [T. B., R. F.]

Alterations of the length of simple repetitive genomic sequences (microsatellite instability, MSI) characterize a distinct mechanism of colorectal carcinogenesis. Such MSI has been found to be associated with hereditary nonpolyposis colorectal cancer (HNPCC) that involves mutation of the human mismatch repair genes hMSH2 and hMLH1 as well as many sporadic cancers of most tissue types. Although the study of MSI status is a useful tool for HNPCC screening and for the determination of tumor prognosis in sporadic cases of colorectal cancer, the reliability of MSI diagnosis is still a subject of debate. Here we have examined 58 primary colorectal tumors (selected from a cohort of 200) using 31 microsatellite markers that comprised the most frequent simple repeat types. The expression of the hMSH2 and hMLH1 mismatch repair proteins was studied by immunohistochemistry, and most patients were surveyed for at least 2 years. Reproducibility of gel interpretation, as well as diagnostic sensitivity and specificity of the MSI status, were determined. We found that unambiguous determination of band shifts as well as MSI diagnosis were closely related to the type of the marker repeat and that MSI could be subdivided into "high" MSI (>20% unstable loci), "low" MSI (<10% unstable loci), and microsatellite stable (0% unstable loci). One-half of the patients with high MSI tumors (n = 8) fulfilled either the Amsterdam criteria (n = 4), had at least one relative with HNPCC-related carcinoma (n = 2), or were diagnosed with colorectal cancer at an age below 45 years (n = 2). Fourteen of the 15 high MSI tumors had lost either hMSH2 (n = 8) or hMLH1 (n = 6) protein expression. In contrast, all of the low MSI tumors and the MSI-negative tumors displayed normal expression of hMSH2 and hMLH1. These studies provide a clear recommendation for the uniform use of a panel of 10 microsatellites and a definition of at least 40% instability (using these defined marker loci) in the diagnostic analysis of MSI.

¹ Supported by Grant Bo 1445/1-2 from the Deutsche Forschungsgemeinschaft, Bonn, Germany (to T. B.), Grant 93.055.2 from the Wilhelm Sander-Stiftung, München, Germany (to J. R.), and NIH Grants CA56542 and CA57007 (to R. F.). Data have been presented in part at the first joint meeting of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer and Leeds Castle Polyposis Group, June 4–7, 1997, Nordwijk, the Netherlands.

² To whom requests for reprints should be addressed, (to R. F.) at Genetics and Molecular Biology Program, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, E-mail: rfishel@hendrix.jci.tju.edu; and/or (to J. R.) at Institut fuer Pathologie, Universitaet Regenburg, Franz-Josef-Strauss-Allee, D-93042 Regensburg, Germany; E-mail: Josef.rueschoff@klinik.uni-regensburg.de.

Received 8/ 5/97. Accepted 9/22/97.

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				A. L. Bacon, M. G. Dunlop, and S. M. Farrington Hypermutability at a poly(A/T) tract in the human germline Nucleic Acids Res., November 1, 2001; 29(21): 4405 - 4413. [Abstract] [Full Text] [PDF]

				T. Kambara, N. Matsubara, H. Nakagawa, K. Notohara, T. Nagasaka, T. Yoshino, H. Isozaki, G. B. Sharp, K. Shimizu, J. Jass, et al. High Frequency of Low-Level Microsatellite Instability in Early Colorectal Cancer Cancer Res., November 1, 2001; 61(21): 7743 - 7746. [Abstract] [Full Text] [PDF]

				J. Raedle, J. Trojan, A. Brieger, N. Weber, D. Schafer, G. Plotz, E. Staib-Sebler, S. Kriener, M. Lorenz, and S. Zeuzem Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer Ann Intern Med, October 16, 2001; 135(8_Part_1): 566 - 576. [Abstract] [Full Text] [PDF]

				W. E. Glaab, R. B. Hill, and T. R. Skopek Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells Carcinogenesis, October 1, 2001; 22(10): 1709 - 1713. [Abstract] [Full Text] [PDF]

				R Ward, A Meagher, I Tomlinson, T O'Connor, M Norrie, R Wu, and N Hawkins Microsatellite instability and the clinicopathological features of sporadic colorectal cancer Gut, June 1, 2001; 48(6): 821 - 829. [Abstract] [Full Text] [PDF]

				A. K. Sood, R. Holmes, M. J. C. Hendrix, and R. E. Buller Application of the National Cancer Institute International Criteria for Determination of Microsatellite Instability in Ovarian Cancer Cancer Res., June 1, 2001; 61(11): 4371 - 4374. [Abstract] [Full Text] [PDF]

				A. Loukola, K. Eklin, P. Laiho, R. Salovaara, P. Kristo, H. Jarvinen, J.-P. Mecklin, V. Launonen, and L. A. Aaltonen Microsatellite Marker Analysis in Screening for Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Cancer Res., June 1, 2001; 61(11): 4545 - 4549. [Abstract] [Full Text] [PDF]

				T. Watanabe, T.-T. Wu, P. J. Catalano, T. Ueki, R. Satriano, D. G. Haller, A. B. Benson, and S. R. Hamilton Molecular Predictors of Survival after Adjuvant Chemotherapy for Colon Cancer N. Engl. J. Med., April 19, 2001; 344(16): 1196 - 1206. [Abstract] [Full Text] [PDF]

				W. S. Samowitz, J. A. Holden, K. Curtin, S. L. Edwards, A. R. Walker, H. A. Lin, M. A. Robertson, M. F. Nichols, K. M. Gruenthal, B. J. Lynch, et al. Inverse Relationship between Microsatellite Instability and K-ras and p53 Gene Alterations in Colon Cancer Am. J. Pathol., April 1, 2001; 158(4): 1517 - 1524. [Abstract] [Full Text] [PDF]

				C. Rengucci, P. Maiolo, L. Saragoni, W. Zoli, D. Amadori, and D. Calistri Multiple Detection of Genetic Alterations in Tumors and Stool Clin. Cancer Res., March 1, 2001; 7(3): 590 - 593. [Abstract] [Full Text]

				V. L. J. Whitehall, M. D. Walsh, J. Young, B. A. Leggett, and J. R. Jass Methylation of O-6-Methylguanine DNA Methyltransferase Characterizes a Subset of Colorectal Cancer with Low-level DNA Microsatellite Instability Cancer Res., February 1, 2001; 61(3): 827 - 830. [Abstract] [Full Text]

				J. Alexander, T. Watanabe, T.-T. Wu, A. Rashid, S. Li, and S. R. Hamilton Histopathological Identification of Colon Cancer with Microsatellite Instability Am. J. Pathol., February 1, 2001; 158(2): 527 - 535. [Abstract] [Full Text] [PDF]

				J. R. Jass, J. Young, B. A. Leggett, N. Hawkins, I. Tomlinson, and R. Ward Biological Significance of Microsatellite Instability-Low (MSI-L) Status in Colorectal Tumors Am. J. Pathol., February 1, 2001; 158(2): 779 - 781. [Full Text] [PDF]

				H. Primdahl, H. von der Maase, M. Christensen, H. Wolf, and T. F. Ørntoft Allelic Deletions of Cell Growth Regulators during Progression of Bladder Cancer Cancer Res., December 1, 2000; 60(23): 6623 - 6629. [Abstract] [Full Text]

				T. Grundei, H. Vogelsang, K. Ott, J. Mueller, M. Scholz, K. Becker, U. Fink, J. R. Siewert, H. Höfler, and G. Keller Loss of Heterozygosity and Microsatellite Instability as Predictive Markers for Neoadjuvant Treatment in Gastric Carcinoma Clin. Cancer Res., December 1, 2000; 6(12): 4782 - 4788. [Abstract] [Full Text]

				H. F. A. Vasen Clinical Diagnosis and Management of Hereditary Colorectal Cancer Syndromes J. Clin. Oncol., November 1, 2000; 18(90001): 81s - 92. [Full Text] [PDF]

				K Shitoh, F Konishi, M Miyaki, T Iijima, T Furukawa, T Tsukamoto, and H Nagai Pathogenesis of non-familial colorectal carcinomas with high microsatellite instability J. Clin. Pathol., November 1, 2000; 53(11): 841 - 845. [Abstract] [Full Text] [PDF]

				S. E. Berry, T. W. Davis, J. E. Schupp, H.-S. Hwang, Niels de Wind, and T. J. Kinsella Selective Radiosensitization of Drug-resistant MutS Homologue-2 (MSH2) Mismatch Repair-deficient Cells by Halogenated Thymidine (dThd) Analogues: Msh2 Mediates dThd Analogue DNA Levels and the Differential Cytotoxicity and Cell Cycle Effects of the dThd Analogues and 6-Thioguanine Cancer Res., October 1, 2000; 60(20): 5773 - 5780. [Abstract] [Full Text]

				P. Starostik, A. Greiner, S. Schwarz, J. Patzner, A. Schultz, and H. K. Muller-Hermelink The Role of Microsatellite Instability in Gastric Low- and High-Grade Lymphoma Development Am. J. Pathol., October 1, 2000; 157(4): 1129 - 1136. [Abstract] [Full Text] [PDF]

				M. J. Sobrido, C. R. Pereira, F. Barros, J. Forteza, A. Carracedo, and M. Lema Low frequency of replication errors in primary nervous system tumours J. Neurol. Neurosurg. Psychiatry, September 1, 2000; 69(3): 369 - 375. [Abstract] [Full Text] [PDF]

				H. B. Salvesen, N. MacDonald, A. Ryan, O. E. Iversen, I. J. Jacobs, L. A. Akslen, and S. Das Methylation of hMLH1 in a Population-based Series of Endometrial Carcinomas Clin. Cancer Res., September 1, 2000; 6(9): 3607 - 3613. [Abstract] [Full Text]

				S. M. Richard, G. Bailliet, G. L. Páez, M. S. Bianchi, P. Peltomäki, and N. O. Bianchi Nuclear and Mitochondrial Genome Instability in Human Breast Cancer Cancer Res., August 1, 2000; 60(15): 4231 - 4237. [Abstract] [Full Text]

				E. Heinmoller, W. Dietmaier, H. Zirngibl, P. Heinmoller, W. Scaringe, K.-W. Jauch, F. Hofstadter, and J. Ruschoff Molecular Analysis of Microdissected Tumors and Preneoplastic Intraductal Lesions in Pancreatic Carcinoma Am. J. Pathol., July 1, 2000; 157(1): 83 - 92. [Abstract] [Full Text] [PDF]

				A. Chao, F. Gilliland, C. Willman, N. Joste, I-M. Chen, N. Stone, J. Ruschulte, D. Viswanatha, P. Duncan, R. Ming, et al. Patient and Tumor Characteristics of Colon Cancers with Microsatellite Instability: A Population-based Study Cancer Epidemiol. Biomarkers Prev., June 1, 2000; 9(6): 539 - 544. [Abstract] [Full Text]

				K Yamashita, Y Arimura, S Kurokawa, F Itoh, T Endo, K Hirata, A Imamura, M Kondo, T Sato, and K Imai Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract Gut, June 1, 2000; 46(6): 790 - 794. [Abstract] [Full Text] [PDF]

				J.-W. Chang, Y.-C. Chen, C.-Y. Chen, J.-T. Chen, S.-K. Chen, and Y.-C. Wang Correlation of Genetic Instability with Mismatch Repair Protein Expression and p53 Mutations in Non-Small Cell Lung Cancer Clin. Cancer Res., May 1, 2000; 6(5): 1639 - 1646. [Abstract] [Full Text] [PDF]

				S. A. Kuismanen, M. T. Holmberg, R. Salovaara, A. de la Chapelle, and P. Peltomaki Genetic and Epigenetic Modification of MLH1 Accounts for a Major Share of Microsatellite-Unstable Colorectal Cancers Am. J. Pathol., May 1, 2000; 156(5): 1773 - 1779. [Abstract] [Full Text] [PDF]

				F. Kullmann, T. Widmann, A. Kirner, H.-P. Jüsten, D. Wessinghage, W. Dietmaier, J. Rüschoff, S. Gay, J. Schölmerich, and U. Müller-Ladner Microsatellite analysis in rheumatoid arthritis synovial fibroblasts Ann Rheum Dis, May 1, 2000; 59(5): 386 - 389. [Abstract] [Full Text]

				I. Gonzalez-Garcia, V. Moreno, M. Navarro, J. Marti-Rague, E. Marcuello, C. Benasco, O. Campos, G. Capella, and M. A. Peinado Standardized Approach for Microsatellite Instability Detection in Colorectal Carcinomas J Natl Cancer Inst, April 5, 2000; 92(7): 544 - 549. [Abstract] [Full Text] [PDF]

				Y. R. Parc, K. C. Halling, L. Wang, E. R. Christensen, J. M. Cunningham, A. J. French, L. J. Burgart, T. L. Price-Troska, P. C. Roche, and S. N. Thibodeau hMSH6 Alterations in Patients with Microsatellite Instability-Low Colorectal Cancer Cancer Res., April 1, 2000; 60(8): 2225 - 2231. [Abstract] [Full Text]

				N. D. MacDonald, H. B. Salvesen, A. Ryan, O.-E. Iversen, L. A. Akslen, and I. J. Jacobs Frequency and Prognostic Impact of Microsatellite Instability in a Large Population-based Study of Endometrial Carcinomas Cancer Res., March 1, 2000; 60(6): 1750 - 1752. [Abstract] [Full Text]

				R. Lowsky, A. Magliocco, R. Ichinohasama, A. Reitmair, S. Scott, M. Henry, M. E. Kadin, and J. F. DeCoteau MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability Blood, March 1, 2000; 95(5): 1767 - 1772. [Abstract] [Full Text] [PDF]