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Overlapping Gene Expression in Fetal Mouse Intestine Development and Human Colorectal Cancer

¹ Dana-Farber Cancer Institute and ² Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Ramesh A. Shivdasani, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-5746; Fax: 617-632-4471; E-mail: ramesh_shivdasani{at}dfci.harvard.edu.

Pathways relevant to cancer are well known to overlap with fetal development, as reflected in reactivation of embryonic genes in tumors. However, molecular evidence for this notion has gathered in piecemeal fashion, and systematic approaches have rarely been applied to gauge the extent and global characteristics of the overlap in gene expression between developing tissues and cancer. The fraction of genes that is expressed aberrantly in a given cancer and also developmental in primary function is unknown, and the tissue specificity of recapitulated gene expression remains unexplored. We developed a statistical method to relate expression profiles from human colon cancer and diverse nonintestinal tumors to transcripts that decline in expression with epithelial differentiation in the fetal mouse gut. For genes that are overexpressed in colon cancer, we computed 8% to 19% likelihood that they were expressed transiently during epithelial morphogenesis in intestine development. Among genes dysregulated in other tumors, the corresponding likelihood fell between 1% and 6%. Similarly, low probabilities were obtained when we compared genes not overexpressed in colon cancer with transcriptional profiles in intestine organogenesis. Genes that increase after fetal gut epithelial differentiation were not differentially represented between cancerous and normal colon. Our findings systematically characterize the global extent and tissue specificity of developmental expression programs in colorectal cancer and illustrate the use of such an approach to identify candidate biomarkers and therapeutic targets.