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Proliferation, Apoptosis, and Survival in High-Level Microsatellite Instability Sporadic Colorectal Cancer¹

Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital Foundation Clinical Research Centre, Herston [J. M. M-R., L. A. S., J. P. Y., B. A. L., G. L. R-S.]; Population and Clinical Sciences Division, Queensland Institute of Medical Research, Brisbane [D. M. P., N. P.]; and Department of Pathology, University of Queensland Medical School, Brisbane [L. E. R., A-E. B-H., M. D. W., J. R. J.], Queensland 4029, Australia

Sporadic colorectal cancer (CRC) characterized by high-level DNA microsatellite instability (MSI-H) has a favorable prognosis. The reason for this MSI-H survival advantage is not known. The aim of this study was to correlate proliferation, apoptosis, and prognosis in CRC stratified by MSI status. The proliferative index (PI) was measured by immunohistochemical staining with the Ki-67 antibody in a selected series of 100 sporadic colorectal cancers classified according to the level of MSI as 31 MSI-H, 29 MSI-Low (MSI-L), and 40 microsatellite stable (MSS). The Ki-67 index was significantly higher in MSI-H cancers (P < 0.0001) in which the PI was 90.1 ± 1.2% (mean ± SE) compared with 69.5 ± 3.1% and 69.5 ± 2.3% in MSI-L and MSS subgroups, respectively. There was a positive linear correlation between the apoptotic index (AI) and PI (r = 0.51; P < 0.001), with MSI-H cancers demonstrating an increased AI:PI ratio indicative of a lower index of cell production. A high PI showed a trend toward predicting improved survival within MSI-H cancers (P = 0.09) but did not predict survival in MSI-L or MSS cancers. The AI was not associated with survival in any MSI subgroup. In conclusion, this is the first study to show that sporadic MSI-H cancers are characterized by a higher AI:PI ratio and increased proliferative activity compared with MSI-L and MSS cancers, and that an elevated PI may confer a survival advantage within the MSI-H subset.

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