Defective DNA Mismatch Repair Determines a Characteristic Transcriptional Profile in Proximal Colon Cancers

Pietro, Massimiliano di; Bellver, J. Sabates; Menigatti, Mirco; Bannwart, Fridolin; Schnider, Annelies; Russell, Anna; Truninger, Kaspar; Jiricny, Josef; Marra, Giancarlo

doi:10.1053/j.gastro.2005.06.028

Cited by 45 publications

(36 citation statements)

References 51 publications

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“…Moreover, when only the colon samples were considered by unsupervised analysis, the tumors segregated into two clusters of roughly equal size (a representative sub-cluster is shown in Figure 4). This clustering of colon samples into two distinct groups may reflect subtypes of colon cancer (eg MMR þ vs MMRÀ) as reported by others, 29 but we believe in part represents an unequal degree of smooth muscle and other stromal contamination of these samples. This conclusion is supported by the finding that the transcripts that best distinguished the two subgroups ( Figure 4) are highly expressed in smooth muscle: eg g-actin, smooth muscle myosin, desmuslin and tropomyosin (smooth muscle transcripts identified using source data of 30 ).…”

Section: Resultssupporting

confidence: 77%

RNA expression analysis of formalin-fixed paraffin-embedded tumors

Penland

Keku

Torrice

et al. 2007

Laboratory Investigation

143

120

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RNA expression analysis is an important tool in cancer research, but a limitation has been the requirement for high-quality RNA, generally derived from frozen samples. Such tumor sets are often small and lack clinical annotation, whereas formalin-fixed paraffin-embedded (FFPE) materials are abundant. Although RT-PCR-based methods from FFPE samples are finding clinical application, genome-wide microarray analysis has proven difficult. Here, we report expression profiling on RNA from 157 FFPE tumors. RNA was extracted from 2-to 8-year-old FFPE or frozen tumors of known and unknown histologies. Total RNA was analyzed, reverse-transcribed and used for the synthesis of labeled aRNA after two rounds of amplification. Labeled aRNA was hybridized to a 3 0 -based 22K spot oligonucleotide arrays, and compared to a labeled reference by two-color microarray analysis. After normalization, gene expression profiles were compared by unsupervised hierarchical clustering. Using this approach, at least 24% of unselected FFPE samples produced RNA of sufficient quality for microarray analysis. From our initial studies, we determined criteria based on spectrophotometric analyses and a novel TaqMan-based assay to predict which samples were of sufficient quality for microarray analysis before hybridization. These criteria were validated on an independent set of tumors with a 100% success rate (20 of 20). Unsupervised analysis of informative gene expression profiles distinguished tumor type and subtype, and identified tumor tissue of origin in three unclassified carcinomas. Although only a minority of FFPE blocks could be analyzed, we show that informative RNA expression analysis can be derived from selected FFPE samples.

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Section: Resultssupporting

confidence: 77%

RNA expression analysis of formalin-fixed paraffin-embedded tumors

Penland

Keku

Torrice

et al. 2007

Laboratory Investigation

143

120

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“…One of the first features that attracted our attention was the marked upregulation of KIAA1199 (Supplementary Table S4), a gene encoding a protein with unknown function. Its overexpression was striking in all colorectal adenomas we examined (average increases of 54.8-fold compared with normal mucosa) and in carcinomas (8). These findings were fully confirmed by realtime reverse transcription-PCR analysis of RNA extracted from samples used for the microarray study and from additional samples collected after the present study was completed ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 76%

“…This gene, which encodes a protein of unknown function, was strikingly overexpressed in all the adenomas included in this study and in 25 adenocarcinomas of the colon described in a previous report (8). Even more intriguingly, its expression was significantly correlated with that of several genes that are well-established targets of Wnt signaling.…”

Section: Mol Cancer Res 2007;5(12) December 2007supporting

confidence: 61%

Transcriptome Profile of Human Colorectal Adenomas

Sabates–Bellver

Flier

Palo

et al. 2007

Molecular Cancer Research

Self Cite

435

389

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Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the B-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation.

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“…2D). The TAZ-AXL-CTGF-high and -low groups were further compared, and differential expression of the MMR-signature-associated genes was identified (8). Thus, the expression levels of genes that are usually overexpressed in MMR-proficient colon cancer, including reduced nicotinamide adenine dinucleotide phosphate oxidase 1, quinolinate phosphoribosyltransferase, 3-hydroxy-3-methylglutaryl-CoA synthase 2, ar ylsulfatase E, γ-glutamyl hydrolase, glutathione peroxidase 2, serine peptidase inhibitor Kazal type 1, transcription factor 7, inhibitor of DNA binding 1, B-cell chronic lymphocytic leukemia/lymphoma 11A, indian hedgehog, guanylate cyclase 2C, protein kinase adenosine monophosphate-activated β 1, Achaete-Scute complex homolog 2, pleiomorphic adenoma gene-like 2, transcription factor-like 5, kinesin family member 3B, villin 1, cadherin, EGF laminin A seven-pass G-type receptor 3, gap junction protein β 1, solute carrier family 5 (sodium/glucose cotransporter) member 1, dipeptidase 1, transmembrane 9 superfamily protein member 4 and family with sequence similarity 3 member A, were reduced in the TAZ-AXL-CTGF-high group, compared with the TAZ-AXL-CTGF-low group.…”

Section: Univariate Analysismentioning

confidence: 99%

Association between the expression levels of TAZ, AXL and CTGF and clinicopathological parameters in patients with colon cancer

et al. 2015

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Abstract.Colon cancer accounts for a large proportion of all the cancer -associated morbidities worldwide. Genetic analysis and stratification of patients based on survival may identify genetic signatures potentially useful for prognostic or treatment planning purposes. Previous studies have reported that the messenger (m)RNA expression levels of tafazzin (TAZ), AXL receptor tyrosine kinase (AXL) and connective tissue growth factor (CTGF) were able to predict the survival of patients with colon cancer in two independent colon cancer datasets. However, limited clinicopathological data were available from these two datasets. By contrast, a large colon cancer dataset comprising 566 patients has been recently published in the Gene Expression Omnibus database, which contains data regarding tumor stage and location, and genetic status of mismatch repair (MMR), Kirsten rat sarcoma viral oncogene homolog (KRAS), B-Raf proto-oncogene serine/threonine kinase (BRAF) and tumor protein p53 (TP53). In the present study, the mRNA expression levels of TAZ, AXL and CTGF were evaluated, and the TAZ-AXL-CTGF signature was correlated with the available pathological parameters and survival data. Overexpression of TAZ, AXL and CTGF was observed to be associated with severe pathological stage, deficiency in MMR, colon cancer subtype C4 and mutations in the BRAF gene. In addition, overexpression of TAZ-AXL-CTGF was associated with short overall survival in patients with mutations in the TP53 gene, colon cancer subtype C6, proficient MMR and wild-type status of the KRAS and BRAF genes. Furthermore, the prognostic value of TAZ-AXL-CTGF overexpression was observed to be independent of all the clinicopathological parameters and mutational statuses analyzed. The results of the present study confirm the previously reported findings, and suggest that the TAZ-AXL-CTGF mRNA signature is a potential prognostic indicator in colon cancer.

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Defective DNA Mismatch Repair Determines a Characteristic Transcriptional Profile in Proximal Colon Cancers

Cited by 45 publications

References 51 publications

RNA expression analysis of formalin-fixed paraffin-embedded tumors

RNA expression analysis of formalin-fixed paraffin-embedded tumors

Transcriptome Profile of Human Colorectal Adenomas

Association between the expression levels of TAZ, AXL and CTGF and clinicopathological parameters in patients with colon cancer

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