Molecular profiling of longitudinally observed small colorectal polyps: a cohort study
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PROVIDER: EGAS00001003284 | EGA |
REPOSITORIES: EGA
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Project description:Sessile serrated adenomas are now recognized as precursor lesions of a substantial subset of colorectal cancers arising via a so-called “serrated pathway”. However, their biological markers remain to be defined. The aim of our study was to identify differentially expressed genes in sessile serrated adenomas, hyperplastic polyps and tubular adenomas. Gene expression analysis demonstrated molecular differences between polyp types. Further studies using QRT-PCR on Cathepsin E demonstrated a significantly (p< 0.05) higher expression in sessile serrated adenomas as compared to both other polyp types. Trefoil Factor 1, showed the same trend of expression for sessile serrated adenomas as compared to hyperplastic polyps, and was significantly higher in both polyps compared to tubular adenomas. Immunohistochemistry for both proteins demonstrated strong cytoplasmic staining of abnormal crypts in all sessile serrated adenomas while staining in tubular adenomas and hyperplastic polyps was weak and focal. BRAF and KRAS mutation analysis were employed to further validate polyp discrimination. The findings demonstrated the positive association of the BRAF mutation, V600E, with sessile serrated adenomas and KRAS mutations with tubular adenomas (P<0.05). This study demonstrates CTSE and TFF1 over-expression in sessile serrated adenomas compared to both hyperplastic polyps and tubular adenomas. Keywords: colonic polyp tissue comparison, linear modelling, SSA
2008-08-27 | GSE12514 | GEO
Project description:Background: Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathological, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. Results: 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 over- and underexpression of 78 known components of this signaling cascade. Conclusions: Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis. Experiment Overall Design: Pedunculated, sporadic colorectal polyps and corresponding normal mucosa were obtained during colonoscopies. The tissues were collected prospectively with informed patient consent and the approval of the local Human Research Ethics Committee.
2008-06-16 | E-GEOD-8671 | biostudies-arrayexpress
Project description:This study was conducted to explore the serum methylome of precancerous lesions belonging to the serrated pathway of colorectal carcinogenesis in a prospective multicentre cohort. Individuals were grouped into five main categories: (i) serrated adenocarcinoma (SAC), (ii) high-risk serrated polyps (HR-SP) comprising traditional serrated adenomas (TSA), sessile serrated lesions (SSL), and serrated polyps (SP) with dysplasia or ≥ 10 mm; (iii) high-risk hyperplastic polyps (HR-HP), defined as HP ≥ 10 mm; (iv) low-risk serrated lesions (LR-SL) including SP without dysplasia < 10 mm and HP < 10 mm; and (v) healthy individuals with no colorectal findings (NCF). First, epigenome-wide methylation levels were quantified in pooled cfDNA samples to characterize the differential methylation profile between no serrated neoplasia (NSN: NCF and LR-SL) and high-risk serrated lesions (HR-SL: HR-HP and HR-SP); concordance with tissue methylation levels was assessed using external datasets. Then, the pathway-specific cfDNA methylation signature was evaluated together with cfDNA pools from the conventional CRC pathway. cfDNA was extracted from serum samples and methylation measurements were assessed with the Infinium MethylationEPIC BeadChip. Data was mainly preprocessed and analyzed with R/Bioconductor packages.
2024-03-01 | GSE199173 | GEO
Project description:Colorectal cancer often arises from adenomatous polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Prediciting which progress to cancer and which remain benign is difficult. We developed a long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apc^Min/+ mice were treated with 4% dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy, and pathology was determined. Serial biopsies of tumors were obtained for immunohistochemistry and gene expression profiling by microarray analysis with Affymetrix Whole Genome array. Tumors (n=424) grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated dynamic growth patterns with higher rates of growth and resolution, while more established tumors tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Differentially expressed genes between adenomas and intramucosal carcinomas were identified. We did not identify differentially expressed genes between early and late biopsies from the same tumor. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features are needed to determine which features can be used to risk-stratify polyps for progress to colorectal cancer and potentially guide prevention strategies.
2014-05-03 | GSE46626 | GEO
Project description:The genetic cause for PPB in association with renal tumor and small bowel polyps remains to be identified. Activation of components of the mTOR signalling pathway in the disease lesions suggests that this signal transduction route may be involved in disease pathogenesis and that rapamycin, an inhibitor of mTOR, might be effective in the treatment of PPB and associated lesions. A combination of molecular cytogenetics and gene-specific mutation screens were performed to search for an underlying genetic cause for PPB in association with small bowel polyps. Immunohistochemical analysis to measure mTOR activation was performed on tissue from renal and lung tumor and small bowel polyps from the index case
2010-04-02 | E-GEOD-15521 | biostudies-arrayexpress
Project description:Colorectal cancer often arises from adenomatous polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Prediciting which progress to cancer and which remain benign is difficult. We developed a long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived Apcin/+ mice were treated with 4% dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy, and pathology was determined. Serial biopsies of tumors were obtained for immunohistochemistry and gene expression profiling by microarray analysis with Affymetrix Whole Genome array. Tumors (n=424) grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated dynamic growth patterns with higher rates of growth and resolution, while more established tumors tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Differentially expressed genes between adenomas and intramucosal carcinomas were identified. We did not identify differentially expressed genes between early and late biopsies from the same tumor. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features are needed to determine which features can be used to risk-stratify polyps for progress to colorectal cancer and potentially guide prevention strategies. F1 (SWR x C57BL/6) Apcin/+ mice who had been given two treatments of 4% dextran sodium sulfate in drinking water at weaning underwent colonoscopy around 80 days of age. Those with distal colonic tumors amenable to biopsy had two biopsies taken at that time. Tumors were monitored by colonoscopy every 14 days. Every 28 days, two additional biopsies were taken of each tumor. This protocol was repeated until mice were moribund. Six tumors were removed after sacrifice. The earliest and latest biopsies of each tumor were selected for RNA extraction and Affymetrix hybridization.
2014-05-03 | E-GEOD-46626 | biostudies-arrayexpress
Project description:Sessile serrated adenomas are now recognized as precursor lesions of a substantial subset of colorectal cancers arising via a so-called “serrated pathway”. However, their biological markers remain to be defined. The aim of our study was to identify differentially expressed genes in sessile serrated adenomas, hyperplastic polyps and tubular adenomas. Gene expression analysis demonstrated molecular differences between polyp types. Further studies using QRT-PCR on Cathepsin E demonstrated a significantly (p< 0.05) higher expression in sessile serrated adenomas as compared to both other polyp types. Trefoil Factor 1, showed the same trend of expression for sessile serrated adenomas as compared to hyperplastic polyps, and was significantly higher in both polyps compared to tubular adenomas. Immunohistochemistry for both proteins demonstrated strong cytoplasmic staining of abnormal crypts in all sessile serrated adenomas while staining in tubular adenomas and hyperplastic polyps was weak and focal. BRAF and KRAS mutation analysis were employed to further validate polyp discrimination. The findings demonstrated the positive association of the BRAF mutation, V600E, with sessile serrated adenomas and KRAS mutations with tubular adenomas (P<0.05). This study demonstrates CTSE and TFF1 over-expression in sessile serrated adenomas compared to both hyperplastic polyps and tubular adenomas. Keywords: colonic polyp tissue comparison, linear modelling, SSA Microarray analysis was performed on 13 SSAs and 11 TAs. SSAs were from 4 males and 9 females (mean age of 75) and TAs were from 5 males and 6 females (mean age of 72). Samples were directly hybridised to each other (SSA versus TA) or to a pooled normal control (SSA versus control). A linear model (Smyth 2004) was fitted to the data bringing together the three contrasts: SSA versus control, TA versus control and SSA versus TA. Human OligoLibrary (Compugen Human Oligo Library (v1) containing 18861 60-mer oligonucleotides, representing approximately 16,000 unique genes) by the Adelaide Microarray Centre (Australia) was used. Slides were scanned using a GenePix 3000B scanner (Axon Instruments, Sunnydale, CA), and the Spot package (CSIRO, Australia) was used to identify spots and estimate fore- and background intensities (using a morphological opening background estimator) (Yang, Buckley et al. 2001; Ritchie 2004). Data analysis was performed in R (www.r-project.org) using the Limma package of Bioconductor (Gentleman, Carey et al. 2004; Smyth 2004). Loess print tip method was used to correct for dye-bias and intensity within each group of adjacent spots printed by one pin (Yang, Dudoit et al. 2002). Linear modelling was performed with the Limma package of Bioconductor (Smyth 2004).
2008-08-26 | E-GEOD-12514 | biostudies-arrayexpress
Project description:Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes. A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers. Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed “loss of gradient” reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 – 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers. We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients.
2020-09-16 | PXD018679 | Pride
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
Project description:In this study we compared gene expression of precancerous SSA/Ps and benign MVHPs with particular focus on genes involved in colorectal cancer. We also identify genes whose expression can be used to differentiate SSA/Ps and MVHPs. These results provide insight into the development of SSA/Ps and illustrates differences between these related colonic polyps. Total RNA from 6 samples of normal colon, 6 microvesicular hyperplastic polyps, and 6 sessile serrated adenomas/polyps were compared
2013-07-09 | E-GEOD-43841 | biostudies-arrayexpress