Cross-Species Comparison of Human and Mouse Intestinal Polyps Reveals Conserved Mechanisms in Adenomatous Polyposis Coli ( APC )-Driven Tumorigenesis

• Published in: The American journal of pathology Vol. 172; no. 5; pp. 1363 - 1380
• Main Authors: Gaspar, Claudia, Cardoso, Joana, Franken, Patrick, Molenaar, Lia, Morreau, Hans, Möslein, Gabriela, Sampson, Julian, Boer, Judith M, de Menezes, Renée X, Fodde, Riccardo
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-05-2008; ASIP; American Society for Investigative Pathology
• Subjects: Adenomatous Polyposis Coli - genetics; Adenomatous Polyposis Coli - metabolism; Adenomatous Polyposis Coli - pathology; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Animals; Biological and medical sciences; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Humans; Intestinal Polyps - genetics; Intestinal Polyps - metabolism; Intestinal Polyps - pathology; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Mutation; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Signal Transduction; Species Specificity; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Human; Rodentia; Tumorigenicity; Familial adenomatous polyposis coli; Carcinogenesis; Mechanism; Genetic disease; Vertebrata; Anatomic pathology; Mammalia; Mouse; Animal; Digestive diseases; Intestinal disease; Intestinal polyp; Species; Comparative study; Tumor suppressor gene
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2008.070851

Expression profiling is a well established tool for the genome-wide analysis of human cancers. However, the high sensitivity of this approach combined with the well known cellular and molecular heterogeneity of cancer often result in extremely complex expression signatures that are difficult to interpret functionally. The majority of sporadic colorectal cancers are triggered by mutations in the adenomatous polyposis coli ( APC ) tumor suppressor gene, leading to the constitutive activation of the Wnt/β-catenin signaling pathway and formation of adenomas. Despite this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate, and malignancy potential. Here, we applied a cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carrying APC germline mutations and from mice carrying a targeted inactivating mutation in the mouse homologue Apc . This comparative approach resulted in the establishment of a conserved signature of 166 genes that were differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analyses of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/β-catenin signaling pathway. Moreover, the conserved signature was able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic inactivation of the MYH gene, supporting the usefulness of such comparisons to discriminate among patients with distinct genetic defects.