Dataset Information

Comprehensive mutation analysis in colorectal flat adenomas.

ABSTRACT:

Background

Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes.

Methods

A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "hot spot" regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (?-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing.

Results

APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p?=?0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes.

Conclusion

The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway.

SUBMITTER: Voorham QJ

PROVIDER: S-EPMC3407043 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Comprehensive mutation analysis in colorectal flat adenomas.

Voorham Quirinus J M QJ Carvalho Beatriz B Spiertz Angela J AJ Claes Bart B Mongera Sandra S van Grieken Nicole C T NC Grabsch Heike H Kliment Martin M Rembacken Bjorn B van de Wiel Mark A MA Quirke Philip P Mulder Chris J J CJ Lambrechts Diether D van Engeland Manon M Meijer Gerrit A GA

PloS one 20120727 7

<h4>Background</h4>Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes.<h4>Methods</h4>A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "hot spot" regions of KRAS, BRAF, PIK3CA and ...[more]

PMID: 22848674

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Project description:BackgroundBiological 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.MethodsUsing 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.ResultsThe 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.ConclusionThe 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.

Project description:BackgroundColorectal cancer is considered as the second most common cancer worldwide. Studies have shown that m6A RNA methylation abnormalities play an important role in the pathogenesis of many human diseases, including cancer. The current study was designed to characterize the mutation of m6A related genes and explore their prognostic role in colorectal cancer.MethodsRNA-seq data and somatic mutation data of TCGA-COAD and TCGA-READ were downloaded from UCSC xena for comprehensive analysis. M6A related genes were selected from previous literatures, including "Writer" protein (METTL3, METTL5, METTL14, METTL16, ZC3H13, RBM15, WTAP, KIAA1429), "Reader" protein YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2, HNRNPC, IGF2BP1, IGF2BP2, IGF2BP3), and "Eraser" protein (FTO, ALKBH5). Kaplan-Meier diagrams were used to explore the correlation between m6A-related genes and colorectal cancer prognosis. The correlations between m6A-related genes and clinical parameters and immune-related indicators were explored by Spearman correlation analysis. And finally, the expression patterns of five key genes (RBMX, FMR1, IGF2BP1, LRPPRC and YTHDC2) were detected by qPCR in CRC specimens.ResultsIn CRC, the expressions of m6A-related genes were significantly different between CRC and normal control except METTL14, YTHDF2, YTHDF3. Some of CRC patients (178 in 536) have a m6A-related genes mutation. ZC3H13 has highest mutation frequency of all m6A-related genes. M6A-related genes mainly enrich in regulation of mRNA metabolic process pathway. Patients with high expressions of FMR1, LRPPRC, METTL14, RBMX, YTHDC2, YTHDF2, YTHDF3 have poor prognosis in CRC. There was a significant correlation between the FMR1, LRPPRC, RBMX, YTHDC2, IGF2BP1 expression and the clinical characteristics of CRC. In addition, these genes are significantly associated with immune-related indicators. According to the expression patterns of FMR1, LRPPRC, RBMX, YTHDC2, and IGF2BP1, patients with CRC were clustered into two groups, and their survival was significantly different. By evaluating the tumor microenvironment in two clusters using ssGSEA, expressions of immune checkpoints and GSVA enrichment analysis, we observed that the immune and stem cell index of two cluster were much different. The qPCR results showed that RBMX expression was markedly elevated in cancerous tissues than in the normal colonic tissues.ConclusionOur study identified novel prognostic markers associated with immune of CRC cancer patients. Moreover, the potential mechanisms of prognostic markers in regulating the etiology of CRC cancer were investigated. These findings enrich our understanding of the relationships between m6a related genes and CRC, and may provide novel ideas in the therapy of CRC patients.

Dataset Information

Comprehensive mutation analysis in colorectal flat adenomas.

Background

Methods

Results

Conclusion

Publications

Comprehensive mutation analysis in colorectal flat adenomas.

Similar Datasets

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