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Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.

ABSTRACT: Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%-35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our rightsided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status. We identified CpG loci and regions consistently hyper-methylated throughout the serrated carcinogenesis spectrum, in both our SSA/P specimens and in serrated cancers. Hyper-methylated CpG loci included the known the tumor suppressor gene RET (p = 5.72 x 10-10), as well as loci in differentially methylated regions for GSG1L, MIR4493, NTNG1, MCIDAS, ZNF568, and RERG. The hyper-methylated loci that we identified help characterize the biology of SSA/P development, and could be useful as therapeutic targets, or for future identification of patients who may benefit from shorter surveillance intervals.

SUBMITTER: Andrew AS

PROVIDER: S-EPMC5372551 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.

Andrew Angeline S AS Baron John A JA Butterly Lynn F LF Suriawinata Arief A AA Tsongalis Gregory J GJ Robinson Christina M CM Amos Christopher I CI

International journal of molecular sciences 20170302 3

Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%-35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We que ...[more]

PMID: 28257124

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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.

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.

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Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.

Publications

Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.

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