Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis
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Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis. / Gerling, Marco; Nousiainen, Kari; Hautaniemi, Sampsa; Krüger, Stefan; Fritzsche, Britta; Homann, Nils; Bruch, Hans-Peter; Auer, Gert; Roblick, Uwe J; Ried, Thomas; Habermann, Jens K.
in: INFLAMM BOWEL DIS, Jahrgang 19, Nr. 4, 05.03.2013, S. 691-703.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung
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TY - JOUR
T1 - Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis
AU - Gerling, Marco
AU - Nousiainen, Kari
AU - Hautaniemi, Sampsa
AU - Krüger, Stefan
AU - Fritzsche, Britta
AU - Homann, Nils
AU - Bruch, Hans-Peter
AU - Auer, Gert
AU - Roblick, Uwe J
AU - Ried, Thomas
AU - Habermann, Jens K
PY - 2013/3/5
Y1 - 2013/3/5
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aneuploidy
KW - Biomarkers, Tumor
KW - Cell Transformation, Neoplastic
KW - Colitis, Ulcerative
KW - Colonic Neoplasms
KW - Female
KW - Gene Expression Profiling
KW - Genomic Instability
KW - Humans
KW - Intestinal Mucosa
KW - Male
KW - Middle Aged
KW - Oligonucleotide Array Sequence Analysis
KW - Precancerous Conditions
KW - Prognosis
KW - RNA, Messenger
KW - Real-Time Polymerase Chain Reaction
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1097/MIB.0b013e31827eeaa4
DO - 10.1097/MIB.0b013e31827eeaa4
M3 - SCORING: Journal article
C2 - 23455720
VL - 19
SP - 691
EP - 703
JO - INFLAMM BOWEL DIS
JF - INFLAMM BOWEL DIS
SN - 1078-0998
IS - 4
ER -