The precise genetic mechanism of malignant transformation in DNA mismatch repair deficient, microsatellite-unstable colorectal cancer (CRC) has yet to be elucidated. We employed cDNA microarray to identify patterns of gene expression among CRC cell lines and to compare directly lines with and without microsatellite instability. This study was undertaken to test the hypothesis that microsatellite-unstable CRC cell lines demonstrate specific patterns of gene expression that differ significantly from those observed among microsatellite-stable CRC. Multiple differential expression patterns were identified. Genes demonstrating differential expression included deleted-in-oral-cancer-1 (DOC-1), a highly conserved growth suppressor. DOC-1 expression correlated with microsatellite status, with significantly decreased expression in microsatellite-unstable cell lines and constitutive expression in microsatellite-stable cell lines. We also observed alterations in the biologic behavior of p12(DOC-1)-deficient cell lines, with increased S phase and decreased apoptosis compared to microsatellite-stable (DOC-1+) cell lines. Transfection of p12(DOC-1) into SW48, which lacks p12(DOC-1) expression, resulted in cell cycle and apoptosis profiles similar to other p12(DOC-1)+ cell lines. These results support the hypothesis that microsatellite-unstable CRC is characterized by novel patterns of gene expression different from those associated with microsatellite-stable CRC, and demonstrate that p12(DOC-1) has tumor suppressor potential in colon epithelial cells.