Background: Malignant transformation in ulcerative colitis (UC) is associated with pronounced chromosomal instability, reflected by aneuploidy. Although aneuploidy can precede primary cancer diagnosis in UC for more than a decade, little is known of its cellular consequences.
Methods: Whole-genome gene expression analysis was applied to noninflamed colon mucosa, mucosal biopsies of patients with UC, and UC-associated carcinomas (UCCs). DNA image cytometry was used to stratify samples into ploidy types. Differentially expressed genes (DEGs) were analyzed by Ingenuity Pathway Analysis and validated by real-time quantitative PCR.
Results: Gene expression changes were more pronounced between normal mucosa and UC (2587 DEGs) than between UC and UCC (827 DEGs). Cytometry identified colitis patients with euploid or aneuploid mucosa biopsies, whereas all UCCs were aneuploid. However, 1749 DEGs distinguished euploid UC and UCCs, whereas only 15 DEGs differentiated aneuploid UC and UCCs. A total of 16 genes were differentially expressed throughout the whole sequence from normal controls to UCCs. Particularly, genes pivotal for chromosome segregation (e.g., SMC3 and NUF2) were differentially regulated along aneuploidy development.
Conclusions: The high number of DEGs between normal mucosa and colitis is dominated by inflammatory-associated genes. Subsequent acquisition of aneuploidy leads to subtle but distinct transcriptional alterations, revealing novel target genes that drive genomic instability and thus carcinogenesis. The gene expression signature of malignant phenotypes in aneuploid UC suggests that these lesions might need to be considered as severe as high-grade dysplasia.
Article first published online 28 February 2013
*Laboratory for Surgical Research, Department of Surgery, University of Lübeck, Lübeck, Germany
†Genetics Department, Center for Cancer Research, National Cancer Institute/National Institutes of Health, Bethesda, Maryland
‡Computational Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Research, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
§Practice for Pathology, Friedrich-Lichtenauer Allee 1, Winsen(Luhe), Germany
‖Medical Clinic II, Hospital Wolfsburg, Wolfsburg, Germany
¶Department of Surgery, University of Lübeck, Lübeck, Germany
**Karolinska Biomic Center, Karolinska Institutet, Stockholm, Sweden
††Department of Surgery, Hospital Wolfsburg, Wolfsburg, Germany.
Reprints: Jens K. Habermann, MD, PhD, Laboratory for Surgical Research, Department of Surgery, University of Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany (e-mail: firstname.lastname@example.org).
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This project was supported by the Werner and Klara Kreitz Foundation, Germany, and the Academy of Finland. M. Gerling received a doctoral stipend of excellence by the University of Lübeck and a travel grant by the German Academic Exchange Service (DAAD).
This study was based on the North German Tumorbank of Colorectal Cancer (DKH #108446) and conducted together with the Surgical Center for Translational Oncology – Lübeck (SCTO-L).
Received June 5, 2012
Accepted June 20, 2012