Unknown,Transcriptomics,Genomics,Proteomics

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DNA copy number changes in colorectal flat adenomas

ABSTRACT: Background & aim: Flat adenomas form a specific phenotype of colorectal adenomas that has been associated with more severe molecular changes and consequently a more aggressive clinical behavior compared to their polypoid counterparts. In the present study we set out to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, i.e. chromosomal instability, between flat and polypoid colorectal adenomas. Methods: Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high resolution arrayCGH platform as well as for mutations in the adenomatous polyposis coli (APC) gene. Gene ontology on the genes located on the significantly different regions was performed. Results: Overall, flat adenomas show similar DNA copy number changes as polypoid adenomas. Patterns of DNA copy number changes differed between the two phenotypes with significantly more frequently loss of 5q14.3 and 5q15-q23.3 in flat adenomas, while loss of 1p36.32-p35.3, 10q25.2-q25.3, 17p12 and chromosome 18 were more frequent in polypoid adenomas. The 5q15-q23.3 region harbors the APC locus, therefore mutation status of APC was investigated, showing significantly less mutations in flat adenomas. Pathway analysis and datamining linked the 5q region to inflammation. Conclusion: These results provide evidence that flat and polypoid adenomas have partly overlapping DNA copy number changes, while alterations more specific to flat adenomas have associations with inflammation. Loss of 5q has been associated with aggressive behavior and this could serve as an explanation for a more aggressive clinical behavior of flat lesions. FFPE colorectal tissue samples of 35 polypoid adenomas and 83 flat adenomas. Test samples were compared to an external pool of normal male/female reference DNA.

ORGANISM(S): Homo sapiens

SUBMITTER: Oscar Krijgsman

PROVIDER: E-GEOD-30479 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Chromosome 5q loss in colorectal flat adenomas.

Voorham Quirinus J M QJ Carvalho Beatriz B Spiertz Angela J AJ van Grieken Nicole C T NC Mongera Sandra S Rondagh Eveline J A EJ van de Wiel Mark A MA Jordanova Ekaterina S ES Jordanova Ekaterina S ES Ylstra Bauke B Kliment Martin M Grabsch Heike H Rembacken Bjorn J BJ Arai Tomio T de Bruïne Adriaan P AP Sanduleanu Silvia S Quirke Philip P Mulder Chris J J CJ van Engeland Manon M Meijer Gerrit A GA

Clinical cancer research : an official journal of the American Association for Cancer Research 20120703 17

<h4>Purpose</h4>Flat adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behavior compared with their polypoid counterparts. Here, we aimed to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, that is, chromosomal instability, between flat and polypoid colorectal adenomas.<h4>Experimental design</h4>Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number chan ...[more]

PMID: 22761468

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Project description:Expression profiling is a well established tool for the genome-wide analysis of the transcriptional activity of human neoplasia. However, the high sensitivity of this approach combined with the well-known cellular and molecular heterogeneity of cancer often result in extremely complex and extended expression signatures of difficult functional interpretation. The majority of sporadic colorectal cancer cases are triggered by mutations in the APC tumor suppressor gene leading to constitutive activation of the Wnt/b-catenin signaling pathway and adenoma formation. Notwithstanding this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate and malignant potential. Here, we applied cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carrying APC germline mutations, and from a mouse model carrying a targeted inactivating mutation in the mouse homologue Apc. This comparative approach resulted in the establishment of a conserved signature encompassing 166 genes differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analysis of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/b-catenin signal transduction pathway, as expected from the selection of APC/Apc-mutant intestinal adenomas. Moreover, the conserved signature is able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic incativation of the MYH gene. Keywords: normal versus tumor comparison; compare expression profiles from microdissected samples with distinct germline mutations (FAP vs. MAP). Here, we report the expression profiles from normal and intestinal adenomatous tissue from FAP (familial adenomatous polyposis) and MAP (MUTY-associated polyposis) patients with established APC and MUTY germline mutations. Total RNA samples were obtianed by laser capture microdissection.

Dataset Information

DNA copy number changes in colorectal flat adenomas

Publications

Chromosome 5q loss in colorectal flat adenomas.

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