Dataset Information

RNA sequencing of sessile serrated colon polyps identifies differentially expressed genes and immunohistochemical markers.

ABSTRACT:

Background

Sessile serrated adenomas/polyps (SSA/Ps) may account for 20-30% of colon cancers. Although large SSA/Ps are generally recognized phenotypically, small (<1 cm) or dysplastic SSA/Ps are difficult to differentiate from hyperplastic or small adenomatous polyps by endoscopy and histopathology. Our aim was to define the comprehensive gene expression phenotype of SSA/Ps to better define this cancer precursor.

Results

RNA sequencing was performed on 5' capped RNA from seven SSA/Ps collected from patients with the serrated polyposis syndrome (SPS) versus eight controls. Highly expressed genes were analyzed by qPCR in additional SSA/Ps, adenomas and controls. The cellular localization and level of gene products were examined by immunohistochemistry in syndromic and sporadic SSA/Ps, adenomatous and hyperplastic polyps and controls. We identified 1,294 differentially expressed annotated genes, with 106 increased ?10-fold, in SSA/Ps compared to controls. Comparing these genes with an array dataset for adenomatous polyps identified 30 protein coding genes uniquely expressed ?10-fold in SSA/Ps. Biological pathways altered in SSA/Ps included mucosal integrity, cell adhesion, and cell development. Marked increased expression of MUC17, the cell junction protein genes VSIG1 and GJB5, and the antiapoptotic gene REG4 were found in SSA/Ps, relative to controls and adenomas, were verified by qPCR analysis of additional SSA/Ps (n?=?21) and adenomas (n?=?10). Immunohistochemical staining of syndromic (n?11) and sporadic SSA/Ps (n?17), adenomatous (n?13) and hyperplastic (n?10) polyps plus controls (n?16) identified unique expression patterns for VSIG1 and MUC17 in SSA/Ps.

Conclusion

A subset of genes and pathways are uniquely increased in SSA/Ps, compared to adenomatous polyps, thus supporting the concept that cancer develops by different pathways in these phenotypically distinct polyps with markedly different gene expression profiles. Immunostaining for a subset of these genes differentiates both syndromic and sporadic SSA/Ps from adenomatous and hyperplastic polyps.

SUBMITTER: Delker DA

PROVIDER: S-EPMC3922809 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

RNA sequencing of sessile serrated colon polyps identifies differentially expressed genes and immunohistochemical markers.

Delker Don A DA McGettigan Brett M BM Kanth Priyanka P Pop Stelian S Neklason Deborah W DW Bronner Mary P MP Burt Randall W RW Hagedorn Curt H CH

PloS one 20140212 2

<h4>Background</h4>Sessile serrated adenomas/polyps (SSA/Ps) may account for 20-30% of colon cancers. Although large SSA/Ps are generally recognized phenotypically, small (<1 cm) or dysplastic SSA/Ps are difficult to differentiate from hyperplastic or small adenomatous polyps by endoscopy and histopathology. Our aim was to define the comprehensive gene expression phenotype of SSA/Ps to better define this cancer precursor.<h4>Results</h4>RNA sequencing was performed on 5' capped RNA from seven SS ...[more]

PMID: 24533081

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Project description:BackgroundSessile serrated adenomas/polyps are distinguished from hyperplastic colonic polyps subjectively by their endoscopic appearance and histological morphology. However, hyperplastic and sessile serrated polyps can have overlapping morphological features resulting in sessile serrated polyps diagnosed as hyperplastic. While sessile serrated polyps can progress into colon cancer, hyperplastic polyps have virtually no risk for colon cancer. Objective measures, differentiating these types of polyps would improve cancer prevention and treatment outcome.MethodsRNA-seq training data set and Affimetrix, Illumina testing data sets were obtained from Gene Expression Omnibus (GEO). RNA-seq single-end reads were filtered with FastX toolkit. Read mapping to the human genome, gene abundance estimation, and differential expression analysis were performed with Tophat-Cufflinks pipeline. Background correction, normalization, and probe summarization steps for Affimetrix arrays were performed using the robust multi-array method (RMA). For Illumina arrays, log2-scale expression data was obtained from GEO. Pathway analysis was implemented using Bioconductor package GSAR. To build a platform-independent molecular classifier that accurately differentiates sessile serrated and hyperplastic polyps we developed a new feature selection step. We also developed a simple procedure to classify new samples as either sessile serrated or hyperplastic with a class probability assigned to the decision, estimated using Cantelli's inequality.ResultsThe classifier trained on RNA-seq data and tested on two independent microarray data sets resulted in zero and three errors. The classifier was further tested using quantitative real-time PCR expression levels of 45 blinded independent formalin-fixed paraffin-embedded specimens and was highly accurate. Pathway analyses have shown that sessile serrated polyps are distinguished from hyperplastic polyps and normal controls by: up-regulation of pathways implicated in proliferation, inflammation, cell-cell adhesion and down-regulation of serine threonine kinase signaling pathway; differential co-expression of pathways regulating cell division, protein trafficking and kinase activities.ConclusionsMost of the differentially expressed pathways are known as hallmarks of cancer and likely to explain why sessile serrated polyps are more prone to neoplastic transformation than hyperplastic. The new molecular classifier includes 13 genes and may facilitate objective differentiation between two polyps.

Project description:Background & aimsSessile serrated polyps (SSPs) could account for a substantial proportion of colorectal cancers. We aimed to increase clarity on SSP prevalence and clinical features.MethodsWe performed a systematic review of MEDLINE, Web of Science, Embase, and Cochrane databases for original studies published in English since 2000. We included studies of different populations (United States general or similar), interventions (colonoscopy, autopsy), comparisons (world regions, alternative polyp definitions, adenoma), outcomes (prevalence, clinical features), and study designs (cross-sectional). Random-effects regression was used for meta-analysis where possible.ResultsWe identified 74 relevant colonoscopy studies. SSP prevalence varied by world region, from 2.6% in Asia (95% confidence interval [CI], 0-5.9) to 10.5% in Australia (95% CI, 2.8-18.2). Prevalence values did not differ significantly between the United States and Europe (P = .51); the pooled prevalence was 4.6% (95% CI, 3.4-5.8), and SSPs accounted for 9.4% of polyps with malignant potential (95% CI, 6.6-12.3). The mean prevalence was higher when assessed through high-performance examinations (9.1%; 95% CI, 4.0-14.2; P = .04) and with an alternative definition of clinically relevant serrated polyps (12.3%; 95% CI, 9.3-15.4; P < .001). Increases in prevalence with age were not statistically significant, and prevalence did not differ significantly by sex. Compared with adenomas, a higher proportion of SSPs were solitary (69.0%; 95% CI, 45.9-92.1; P = .08), with diameters of 10 mm or more (19.3%; 95% CI, 12.4-26.2; P = .13) and were proximal (71.5%; 95% CI, 63.5-79.5; P = .008). The mean ages for detection of SSP without dysplasia, with any or low-grade dysplasia, and with high-grade dysplasia were 60.8 years, 65.6 years, and 70.2 years, respectively. The range for proportions of SSPs with dysplasia was 3.7%-42.9% across studies, possibly reflecting different study populations.ConclusionsIn a systematic review, we found that SSPs are relatively uncommon compared with adenoma. More research is needed on appropriate diagnostic criteria, variations in detection, and long-term risk.

Dataset Information

RNA sequencing of sessile serrated colon polyps identifies differentially expressed genes and immunohistochemical markers.

Background

Results

Conclusion

Publications

RNA sequencing of sessile serrated colon polyps identifies differentially expressed genes and immunohistochemical markers.

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