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[Cancer Research 57, 4749-4756, November 1, 1997]
© 1997 American Association for Cancer Research
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Diagnostic Microsatellite Instability: Definition and Correlation with Mismatch Repair Protein Expression1

Wolfgang Dietmaier, Sabine Wallinger, Tina Bocker, Frank Kullmann, Richard Fishel2 and Josef Rüschoff2

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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P. Laiho, V. Launonen, P. Lahermo, M. Esteller, M. Guo, J. G. Herman, J.-P. Mecklin, H. Jarvinen, P. Sistonen, K.-M. Kim, et al.
Low-Level Microsatellite Instability in Most Colorectal Carcinomas
Cancer Res., February 1, 2002; 62(4): 1166 - 1170.
[Abstract] [Full Text] [PDF]

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S. Halford, P. Sasieni, A. Rowan, H. Wasan, W. Bodmer, I. Talbot, N. Hawkins, R. Ward, and I. Tomlinson
Low-Level Microsatellite Instability Occurs in Most Colorectal Cancers and Is a Nonrandomly Distributed Quantitative Trait
Cancer Res., January 1, 2002; 62(1): 53 - 57.
[Abstract] [Full Text] [PDF]

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I. Stefansson, L. A. Akslen, N. MacDonald, A. Ryan, S. Das, I. J. Jacobs, and H. B. Salvesen
Loss of hMSH2 and hMSH6 Expression Is Frequent in Sporadic Endometrial Carcinomas with Microsatellite Instability: A Population-based Study
Clin. Cancer Res., January 1, 2002; 8(1): 138 - 143.
[Abstract] [Full Text] [PDF]