Both human CRCs and mouse colon tumors reactivate an embryonic gene signature. When human and murine tumors are compared, they both broadly re-express an embryonic gene expression pattern. Gene expression profiles from the mouse tumor models and human CRC samples were combined into a single non-redundant gene ortholog genome table structure and subjected to comparative profile analysis. Informative probe-sets from human and mouse platforms were selected, mapped to corresponding ortholog genes, and used to populate a table in which normalized expression for each gene is relative to normal adult colon. (a) Heatmap plot for all cross-species gene orthologs both present and successfully measured on both the Affymetrix Hg-U133 and Vanderbilt Mouse NIA 20 K microarrays (n = 8,621 features). This representation suggests that a large number of human CRC signatures exhibit similar behaviors in the mouse tumors and during embryonic mouse colon development (sidebar: 1,080 (red) and 431 (green) gene lists from (b)). (b) Based on results in (a), four separate gene lists were generated with criteria of over- or under-expression in development or over-expression or under-expression in human CRCs (2,718, 2,365, 2,212, and 737, respectively, with the overlaps shown as a sidebar in (a); red, 1,080 transcripts, and green, 431 transcripts). Genes over-expressed and under-expressed in embryonic mouse colon and human CRCs were found to be over-represented as determined by Fisher's exact test analysis (*p < 7 × 10-88, **p < 1 × 10-76, ***p < 5 × 10-4, ****p < 1 × 10-76). (c) Heatmap plot of all genes co-regulated in human CRCs and during early (ED) and late (LD) mouse embryonic colon development (n = 2,216 features). Six predominant clusters (C18-C23) characterize the transcriptional relationship between human CRC and mouse colon tumor models and embryonic development. Two clusters (C20 and 21) primarily distinguish human CRCs from murine tumors (A, M, S and T). For example, CRC up-regulated transcripts that are either developmentally up- or down-regulated are represented by cluster C22 (n = 860 features) and clusters C21/C23 (n = 142 features), respectively. Conversely, CRC down-regulated transcripts that are either down- or up-regulated during development are shown in clusters C18/C19 (n = 258 features) and cluster C20 (n = 42 features), respectively. Interestingly, while approximately 80% and approximately 60% of genes up- and down-regulated in both human CRCs and mouse development were also up- and down-regulated in tumors from the various mouse models, several clusters provide very interesting exceptions: cluster C20 comprises genes down-regulated in human CRCs that are routinely over-expressed in mouse tumors and development; cluster C21 comprises genes robustly expressed in human CRC that are rarely expressed in embryonic colon or murine tumors. Sample groups: ED, early development (E13.5-E15.5); LD, late development (E16.5-E18.5); A, AOM-induced; M, ApcMin/+; T, Tgfb1-/-; Rag2-/-; S, Smad3-/-. Tissue groups: AC, adult colon; CRC, human CRC. Staging: nAC, normal colon.