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Low Microsatellite Instability Is Associated With Poor Prognosis in Stage C Colon Cancer

From the Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, University of New South Wales; Disciplines of Medicine and Pathology, University of Sydney; Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital; Department of Anatomical Pathology, Concord Hospital; and Department of Colorectal Surgery, Concord Hospital and University of Sydney, Sydney, Australia

Address reprint requests to Maija Kohonen-Corish, PhD, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney NSW 2010, Australia; e-mail: m.corish{at}garvan.org.au

PURPOSE: The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O⁶-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer.

PATIENTS AND METHODS: The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation.

RESULTS: We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival.

CONCLUSION: MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.

Supported by Strathfield Private Hospital Strathfield, Sydney, Australia.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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