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. 2013 Mar-Apr;19(4):691-703.
doi: 10.1097/MIB.0b013e31827eeaa4.

Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis

Marco Gerling  1 , Kari Nousiainen, Sampsa Hautaniemi, Stefan Krüger, Britta Fritzsche, Nils Homann, Hans-Peter Bruch, Gert Auer, Uwe J Roblick, Thomas Ried, Jens K Habermann
Affiliations

Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis

Marco Gerling et al. Inflamm Bowel Dis. 2013 Mar-Apr.

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.

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Figures

FIGURE 1.
FIGURE 1.
Study design and group comparisons. DEGs are given according to the statistic threshold defined in detail in the text. For the comparison of diploid and aneuploid UC mucosa, no DEG was found when applying multiple test statistics. However, 232 genes were found using the uncorrected P value; 5 genes were successfully validated using RT-PCR (genes for which RT-PCR was performed are given in italic where applicable).
FIGURE 2.
FIGURE 2.
Highest ranked network of DEGs between normal controls versus UC (A), and UC versus UCC (B). CP, canonical pathway; Fx, function. Green color denotes upregulation, red color denotes downregulation in UC mucosa (A) or UCC (B).
FIGURE 3.
FIGURE 3.
Genes validated with RT-qPCR. PCR expression was normalized to HGK (PGK1). Error bars represent standard error of the means. A, DEGs between diploid (n = 7) and aneuploid (n = 7) mucosa biopsies. B, DEGs between aneuploid (n = 10) mucosa biopsies and carcinomas (n = 5). C, Genes constantly differentially regulated among the sequence from normal controls (n = 9), through diploid (n = 8) and aneuploid (n = 11) mucosa to UCCs (n = 5). Significant differences between reference group and the so-marked group were indicated with *P < 0.05, **P < 0.01, and ***P < 0.001.
FIGURE 4.
FIGURE 4.
A, IPA network 1 (score 35) of constantly upregulated and downregulated genes across malignant transformation from normal controls to UCC. Red highlighted genes were constantly upregulated over the sequence, and green highlighted genes constantly downregulated. P53, TGFb1, and NF-kB are central nodes of this network as well as canonical pathway (CPs) and common functions (Fx) of genes involved in Wnt/b-catenin signaling, CRC-metastasis signaling, cell proliferation, and aneuploidy. B, Top-rated network of IPA analysis diploid versus aneuploid. Genes involved in canonical pathways such as CRC-metastasis, apoptosis signaling, and production of reactive oxygen species are noted. Remarkably, genes known to function in metastatic spread of CRCs are found in both analyses. Genes participating in this pathway are highlighted in light blue. CP, canonical pathway; Fx, function. Green color denotes constant upregulation (A) or upregulation in aneuploid mucosa (B); red color denotes constant downregulation (A) or downregulation in aneuploid mucosa (B).
FIGURE 5.
FIGURE 5.
Involvement of validated genes in cell cycle and mitosis. Upper part magnifies steps during mitosis and highlights validated genes associated with mitotic dysfunction in red. SMC3 is essential for chromatid cohesion, and aberrant expression might cause chromosome segregation errors. KIF20B is pivotal for the last step of mitosis, cytokinesis. SMARCA1 influences transcription in decondensed chromatin through nucleosome repositioning. Lower part of the image shows cell cycle progression from mitosis through G1/G2 phases onward to G2. Kinetochore proteins are given in boxes indicating their expression during respective phases of the cycle. NUF2 and CENP-H are found to be differentially expressed in our data set and highlighted in red.
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