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Cancer Genes and Genomics

Transcriptome Profile of Human Colorectal Adenomas

¹ Institute of Molecular Cancer Research, ² Institute of Anatomy, and ³ Functional Genomic Center, University of Zurich, Zurich, Switzerland; ⁴ Hubrecht Institute, Netherlands Institute for Developmental Biology, Utrecht, the Netherlands; ⁵ Gastroenterology Unit and ⁶ Pathology Department, Belcolle Hospital, Viterbo, Italy; ⁷ Institute of Biochemistry and Genetics and ⁸ Division of Medical Genetics, University of Basel, Basel, Switzerland; and ⁹ Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, Warsaw, Poland

Requests for reprints: Giancarlo Marra, Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Phone: 41-044-635-3472; Fax: 41-044-635-3484. E-mail: marra{at}imcr.uzh.ch

Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the β-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation. (Mol Cancer Res 2007;5(12):1263–75)

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