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[Cancer Research 58, 5248-5257, November 15, 1998]
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A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of Microsatellite Instability in Colorectal Cancer

C. Richard Boland1, Stephen N. Thibodeau, Stanley R. Hamilton, David Sidransky, James R. Eshleman, Randall W. Burt, Stephen J. Meltzer, Miguel A. Rodriguez-Bigas, Riccardo Fodde, G. Nadia Ranzani and Sudhir Srivastava2

University of California, San Diego, La Jolla, California 92093-0688 [C. R. B.]; Molecular Genetics Laboratory, Mayo Clinic, Rochester, Minnesota 55905 [S. N. T.]; School of Medicine [S. R. H., J. R. E.] and Head & Neck Cancer Research [D. S.], Johns Hopkins University, Baltimore, Maryland 21205-2196; University of Utah Health Sciences Center, Salt Lake City, Utah 84132 [R. W. B.]; University of Maryland Hospital, Baltimore, Maryland 21201 [S. J. M.]; Department of Surgery, Roswell Park Cancer Institute, Buffalo, New York 14263 [M. A. R-B.]; Department of Human Genetics, Leiden University, Leiden AL 2333, the Netherlands [R. F.]; Department of Genetics and Microbiology, University of Pavia, 27100 Pavia, Italy [G. N. R.]; and Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892-7346 [S. S.]

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise ~15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

1 To whom correspondence should be addressed, at University of California, San Diego, 4028 BSB, 9500 Gilman Drive, La Jolla, CA 92093-0688. E-mail: crboland@ucsd.edu.

2 To whom requests for reprints should be addressed, at EPN-330F, 6130 Executive Blvd., NCl, NIH, Bethesda, MD 20892.

Received 2/26/98. Accepted 9/ 9/98.




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JAMA, September 27, 2006; 296(12): 1479 - 1487.
[Abstract] [Full Text] [PDF]

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J. M. Ford and A. S. Whittemore
Predicting and preventing hereditary colorectal cancer.
JAMA, September 27, 2006; 296(12): 1521 - 1523.
[Full Text] [PDF]