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Molecular Biology and Genetics |
Department of Medicine, Division of Gastroenterology [Y. M., F. M. S., F. S., J. Y., Y. X., A. O., E. D., S. W., J. M. A., S. J. M.] and Department of Surgery [D. S.], University of Maryland School of Medicine and Greenebaum Cancer Center and Baltimore VA Hospital, Baltimore, Maryland 21201; Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research, Queensland 4029, Australia [L. A. S., J. Y., B. L.]; Queensland Centre for Schizophrenia Research, The Park Centre for Mental Health, Queensland 4076, Australia [J. M. T.]; and Department of Pathology, McGill University, Montreal, Quebec H3A 2B4, Canada [J. R. J.]
Frequent microsatellite instability MSI (MSI-H) occurring in human tumors is characterized by defective DNA mismatch repair and unique clinical features. However, infrequent MSI (MSI-L) has not been attributable to any other defined molecular pathway, and its existence as a biologically distinct category has been challenged. Moreover, the global molecular phenotypes (GMPs) underlying MSI-H, MSI-L, or microsatellite-stable (MSS) tumors have never been evaluated. To evaluate the impact of MSI status on GMP and to determine the importance of MSI relative to other molecular and clinical features, cDNA microarray-derived data from 41 colon cancers were interpreted using principal components analysis. The clinically relevant principal component with the greatest impact on GMP was component 3, which distinguished MSI-H from non-MSI-H (i.e., MSI-L and microsatellite stable) tumors and was designated the MSI-H separator. Notably, MSI-L cancers were also clearly distinguished from non-MSI-L tumors by another principle component, component 10 (the "MSI-L separator"). This second finding validates the existence of MSI-L tumors as a distinct molecular phenotypic category. Thus, both components 3 and 10 reflected different aspects of MSI and helped to establish principal components analysis as a useful tool to identify and characterize distinct biological features of human malignancy.
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