title: Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis.
abstract: 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.
authors: Laboratory for Surgical Research, Department of Surgery, University of Lübeck, Lübeck, Germany.
authors: Marco
authors: M
authors: Gerling
authors: Kari
authors: K
authors: Nousiainen
authors: Sampsa
authors: S
authors: Hautaniemi
authors: Stefan
authors: S
authors: Krüger
authors: Britta
authors: B
authors: Fritzsche
authors: Nils
authors: N
authors: Homann
authors: Hans-Peter
authors: HP
authors: Bruch
authors: Gert
authors: G
authors: Auer
authors: Uwe J
authors: UJ
authors: Roblick
authors: Thomas
authors: T
authors: Ried
authors: Jens K
authors: JK
authors: Habermann
mesh_terms: D000328:Adult; D000368:Aged; D000782:Aneuploidy; D014408:Biomarkers, Tumor / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000150:complications* / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000209:etiology* / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger