A comprehensive look at transcription factor gene expression changes in colorectal adenomas.
BACKGROUND
Biological processes are controlled by transcription networks. Expression changes of transcription factor (TF) genes in precancerous lesions are therefore crucial events in tumorigenesis. Our aim was to obtain a comprehensive picture of these changes in colorectal adenomas.


METHODS
Using a 3-pronged selection procedure, we analyzed transcriptomic data on 34 human tissue samples (17 adenomas and paired samples of normal mucosa, all collected with ethics committee approval and written, informed patient consent) to identify TFs with highly significant tumor-associated gene expression changes whose potential roles in colorectal tumorigenesis have been under-researched. Microarray data were subjected to stringent statistical analysis of TF expression in tumor vs. normal tissues, MetaCore-mediated identification of TF networks displaying enrichment for genes that were differentially expressed in tumors, and a novel quantitative analysis of the publications examining the TF genes' roles in colorectal tumorigenesis.


RESULTS
The 261 TF genes identified with this procedure included DACH1, which plays essential roles in the proper proliferation and differentiation of retinal and leg precursor cell populations in Drosophila melanogaster. Its possible roles in colorectal tumorigenesis are completely unknown, but it was found to be markedly overexpressed (mRNA and protein) in all colorectal adenomas and in most colorectal carcinomas. However, DACH1 expression was absent in some carcinomas, most of which were DNA mismatch-repair deficient. When networks were built using the set of TF genes identified by all three selection procedures, as well as the entire set of transcriptomic changes in adenomas, five hub genes (TGFB1, BIRC5, MYB, NR3C1, and TERT) where identified as putatively crucial components of the adenomatous transformation process.


CONCLUSIONS
The transcription-regulating network of colorectal adenomas (compared with that of normal colorectal mucosa) is characterized by significantly altered expression of over 250 TF genes, many of which have never been investigated in relation to colorectal tumorigenesis.
Janine
J
Vonlanthen
Michal J
MJ
Okoniewski
Mirco
M
Menigatti
Elisa
E
Cattaneo
Daniela
D
Pellegrini-Ochsner
Ritva
R
Haider
Josef
J
Jiricny
Teresa
T
Staiano
Federico
F
Buffoli
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, Zurich 8051, Switzerland. marra@imcr.uzh.ch.
Giancarlo
G
Marra
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020570:Genes, myb; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; C486747:DACH1 protein, human; D005136:Eye Proteins; D051034:Inhibitor of Apoptosis Proteins; C497713:NR3C1 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D000077022:Survivin; C508960:TGFB1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C509186:TERT protein, human; D019098:Telomerase