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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30479 | GEO | 2012/10/04

SECONDARY ACCESSION(S): PRJNA143465

REPOSITORIES: GEO

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DNA copy number changes in colorectal flat adenomas

Project description: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.

2012-10-04 | E-GEOD-30479 | biostudies-arrayexpress

Homo sapiens

Project description:DNA copy number changes in colorectal flat adenomas

| PRJNA143465 | ENA

Genome-wide mapping of Rad21 binding sites and gene expression profiling in wild type mouse small intestinal epithelial crypts and Apc Min adenomas

Project description:To investigate the role of RAD21 in the transcriptional regulation of global gene expression at early stage of colorectal cancer developments, we peformed the genome-wide analysis to map genomic regions bound by Rad21 in normal small testinal crypts and tumors (adenomas) harvested from Apc Min/+ mice using ChIP-seq. ChIP-seq naalysis identified high confidence RAD21 binding sites unique to normal crypts or adenomas, as well as those common to both tissues. We further performed RNA-seq to profile the changes in gene expression from normal WT crypts to adenomas at the very early stage of adenomagenesis in the context of Rad21 heterozygous loss. mRNA profiles of normal small intestinal crypts (WT) and adenomas from Apc Min/+ and Apc Min/+:Rad21+/- double mutant mouse; Mapping of Rad21 genomic binding sites in normal intestinal crypts (WT) and Apc Min/+ adenomas

2014-10-31 | E-GEOD-59283 | biostudies-arrayexpress

Loss of the mitochondrial pyruvate carrier promotes stem cell gene expression in colon adenomas.

Project description:Loss of the mitochondrial pyruvate carrier promotes stem cell gene expression in AOMDSS colon adenomas, though loss of Apc promotes a more unified pehnotype.

2019-09-02 | GSE136710 | GEO

Array comparative genomic hybridization analysis reveals a limited number of genomic alterations in familial adenomatous polyposis-associated and sporadic desmoid tumors

Project description:Desmoid tumors (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumors arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most non-FAP (sporadic) desmoids carry somatic mutations in the beta-catenin gene. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumors. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumors, we analyzed 17 FAP-associated and 38 sporadic desmoids for copy number abnormalities (CNAs) by means of array comparative genomic hybridization and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Common gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumors. Frequent common losses were observed within a 700 kb region at 5q22.2, comprising the APC gene (11%), in a 2 Mb region at 6p21.2-p21.1 (15%), and in a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of CNAs (59%) than the sporadic tumors (37%). As predicted by the APC germline mutations among these patients, a relatively high percentage (29%) of the FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumors. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumor progression.

2012-04-01 | GSE28458 | GEO

miRNA expression in human colitis-associated dysplasia

Project description:Patients with ulcerative colitis (UC) are at increased risk of colorectal cancer (CRC). Colitis-associated dysplasia (flat or polypoid) continues to be a reliable marker for CRC in these patients. However, flat lesions are often missed during endoscopy and can rapidly progress to high-grade dysplasia or cancer. microRNAs (miRs), small non-coding RNAs, have emerged as a valuable diagnostic biomarker of human cancer due to their ease of detection and stability. The goal of this study was to identify a miR signature that can serve as a reliable biomarker for the early detection of colitis-associated dysplasia in patients with long-standing colitis.

2022-07-23 | GSE209581 | GEO

Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant

Project description:Gastric adenocarcinoma and proximal polyposis of the stomach is an autosomal dominant cancer predisposition syndrome of fundic gland polyposis with a significant risk of gastric adenocarcinoma. We mapped the gene to 5q22 and found loss of heterozygosity (LOH) only on 5q in fundic gland polyps from affected individuals. Sanger sequencing revealed novel point mutations in APC promoter 1B that co-segregated with disease. All three mutations reduced binding of YY1, and all three mutations showed abrogated activity of the APC promoter 1B luciferase assays. Whole genome sequencing of fundic gland polyps without 5q LOH identified somatic truncating mutations in APC.

2016-08-01 | GSE73547 | GEO

Flat colorectal cancer precursor lesions: epidemiological aspects and molecular analysis.

Project description:Interventions: 1. Clinical data registration; 2. Molecular analysis of polypoid vs. flat colorectal lesions. Primary outcome(s): 1. Prevalence of flat colorectal lesions in a Dutch population; 2. Clinical characteristics (e.g. location of lesions, percentage of high-grade dysplasia or early cancer); 3. Molecular charcteristics (epigenetic: methylation status and genetic) of flat vs. polypoid colorectal lesions; 4. Prevalence of flat advanced colorectal cancers vs. polypoid advanced colorecal cancers: clinical features of these lesions (e.g. tumor stage); 5. Relation between serrated and adenomatous polyps. Study Design: Non-randomized controlled trial, Open (masking not used), N/A , unknown, Factorial

| 16199 | ecrin-mdr-crc

Transcriptional profiling of SI adenomas in Apc floxed mice

Project description:Small intestinal adenomas in mice with Apc deficiency following tamoxifen-induced genetic recombination.

2021-02-19 | GSE167008 | GEO

Bcl9 and Pygo synergize downstream of Apc to effect intestinal neoplasia in mouse models recapitulating Familial Adenomatous Polyposis (RNA-Seq)

Project description:We assessed differential gene expression using RNAseq in intestinal adenomas between Apc loss-of-function (Apcmin) mice, or by Apc1322T mice encoding a partially-functional Apc truncation commonly found in colorectal carcinomas.

2018-12-31 | GSE121142 | GEO

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