Published online before print April 10, 2008

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2008.070851v1 172/5/1363    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gaspar, C. Articles by Fodde, R. Search for Related Content PubMed PubMed Citation Articles by Gaspar, C. Articles by Fodde, R.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070851

Accepted for publication January 17, 2008.

Article

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

Claudia Gaspar^*, Joana Cardoso^*, Patrick Franken^*, Lia Molenaar^*, Hans Morreau, Gabriela Möslein^¶, Julian Sampson^||, Judith M. Boer, Renée X. de Menezes, and Riccardo Fodde^*@

From the Department of Pathology,* Josephine Nefkens Institute, and Department of Pediatric Oncology, Erasmus Medical Center, Rotterdam, The Netherlands; Center for Human & Clinical Genetics, and Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands;St. Josefs-Hospital Bochum-Linden,^¶ Bochum, Germany; and Institute of Medical Genetics,^|| Cardiff University, Cardiff, United Kingdom

^@ To whom correspondence should be addressed. E-mail: r.fodde{at}erasmusmc.nl.

	Abstract

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/-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/-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.

This article has been cited by other articles:

				S. Segditsas, O. Sieber, M. Deheragoda, P. East, A. Rowan, R. Jeffery, E. Nye, S. Clark, B. Spencer-Dene, G. Stamp, et al. Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice Hum. Mol. Genet., December 15, 2008; 17(24): 3864 - 3875. [Abstract] [Full Text] [PDF]

				M. H. Kucherlapati, K. Yang, K. Fan, M. Kuraguchi, D. Sonkin, A. Rosulek, M. Lipkin, R. T. Bronson, B. J. Aronow, and R. Kucherlapati Loss of Rb1 in the gastrointestinal tract of Apc1638N mice promotes tumors of the cecum and proximal colon PNAS, October 7, 2008; 105(40): 15493 - 15498. [Abstract] [Full Text] [PDF]