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Automated, Multiplex Assay for High-Frequency Microsatellite Instability in Colorectal Cancer

G.M. Nash, M. Gimbel, J. Shia, A.T. Culliford, D.R. Nathanson, M. Ndubuisi, Y. Yamaguchi, Z.S. Zeng, F. Barany, P.B. Paty

From the Departments of Surgery and Pathology, Memorial Sloan-Kettering Cancer Center, New York; and the Department of Microbiology, Weill Medical College of Cornell University, Ithaca, NY.

Address reprint requests to Philip B. Paty, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: patyp{at}mskcc.org.

Purpose: In a series of hereditary nonpolyposis colorectal cancer (HNPCC) patients, we evaluated the sensitivities of the individual microsatellites recommended by the National Cancer Institute (NCI) consensus workshop for detection of high-frequency microsatellite instability (MSI-H). On the basis of this evaluation, we developed a three-marker assay that assigns microsatellite instability (MSI) in a multiplex polymerase chain reaction.

Methods: Individual marker sensitivity was assessed in 18 HNPCC tumors. Multiplex and NCI assays were then assessed in a series of 120 patients with early-onset colon cancer.

Results: The sensitivity of microsatellite markers BAT25, BAT26, D2S123, D5S346, and D17S250 for ASI in HNPCC cancers was 100%, 94%, 72%, 50%, and 50%, respectively. The three most accurate markers were combined and optimized in a multiplex assay that assigned MSI-H whenever at least two of three markers revealed ASI. In early-onset colon cancers, the prevalence of MSI-H determined by the multiplex assay and by the NCI assay was 16% and 23%, respectively. The additional MSI-H tumors and patients with MSI-H identified by the NCI assay lacked the traits characteristic of MSI-H seen in tumors and patients identified by the multiplex assay: retention of heterozygosity (NCI additional 22% v multiplex 84%; P = .003), characteristic tumor morphology (0% v 64%; P = .006), and 5-year cancer survival rate (44% v 100%; P = .0003).

Conclusion: The multiplex assay identifies colon cancers with MSI-H by assessing three highly accurate microsatellite markers. This assay identifies a smaller MSI-H cohort with more homogeneous clinical features and is superior as a marker of favorable prognosis. It merits prospective evaluation as a marker of prognosis and as a screening test for HNPCC.

Supported by a grant from the National Cancer Institute (2 P01 CA65930-05A2) and by the philanthropy of Marie and William Bianco.

This work was presented, in part, as a poster at the May 2002 meeting of the American Society of Clinical Oncology under the title, "An Objective, Multiplex Microsatellite Instability (MSI) Assay for Colorectal Adenocarcinoma."

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