Dataset Information

CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps.

ABSTRACT: BACKGROUND:Although colorectal sessile serrated adenomas/polyps (SSA/Ps) with morphologic dysplasia are regarded as definite high-risk premalignant lesions, no reliable grading or risk-stratifying system exists for non-dysplastic SSA/Ps. The accumulation of CpG island methylation is a molecular hallmark of progression of SSA/Ps. Thus, we decided to classify non-dysplastic SSA/Ps into risk subgroups based on the extent of CpG island methylation. METHODS:The CpG island methylator phenotype (CIMP) status of 132 non-dysplastic SSA/Ps was determined using eight CIMP-specific promoter markers. SSA/Ps with CIMP-high and/or MLH1 promoter methylation were regarded as a high-risk subgroup. RESULTS:Based on the CIMP analysis results, methylation frequency of each CIMP marker suggested a sequential pattern of CpG island methylation during progression of SSA/P, indicating MLH1 as a late-methylated marker. Among the 132 non-dysplastic SSA/Ps, 34 (26%) were determined to be high-risk lesions (33 CIMP-high and 8 MLH1-methylated cases; seven cases overlapped). All 34 high-risk SSA/Ps were located exclusively in the proximal colon (100%, p = .001) and were significantly associated with older age (≥ 50 years, 100%; p = .003) and a larger histologically measured lesion size (> 5 mm, 100%; p = .004). In addition, the high-risk SSA/Ps were characterized by a relatively higher number of typical base-dilated serrated crypts. CONCLUSIONS:Both CIMP-high and MLH1 methylation are late-step molecular events during progression of SSA/Ps and rarely occur in SSA/Ps of young patients. Comprehensive consideration of age (≥ 50), location (proximal colon), and histologic size (> 5 mm) may be important for the prediction of high-risk lesions among non-dysplastic SSA/Ps.

SUBMITTER: Lee JA

PROVIDER: S-EPMC6639709 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps.

Lee Ji Ae JA Park Hye Eun HE Yoo Seung-Yeon SY Jeong Seorin S Cho Nam-Yun NY Kang Gyeong Hoon GH Kim Jung Ho JH

Journal of pathology and translational medicine 20190319 4

<h4>Background</h4>Although colorectal sessile serrated adenomas/polyps (SSA/Ps) with morphologic dysplasia are regarded as definite high-risk premalignant lesions, no reliable grading or risk-stratifying system exists for non-dysplastic SSA/Ps. The accumulation of CpG island methylation is a molecular hallmark of progression of SSA/Ps. Thus, we decided to classify non-dysplastic SSA/Ps into risk subgroups based on the extent of CpG island methylation.<h4>Methods</h4>The CpG island methylator ph ...[more]

PMID: 30887794

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Project description:ImportanceResearch demonstrates adenoma detection rate (ADR) and proximal sessile serrated polyp detection rate (pSSPDR) are associated with endoscopist characteristics including sex, specialty, and years in practice. However, many studies have not adjusted for other risk factors associated with colonic neoplasia.ObjectiveTo assess the association between endoscopist characteristics and polyp detection after adjusting the factors included in previous studies as well as other factors.Design, setting, and participantsThis cohort study was conducted in the Cleveland Clinic health system with data from individuals undergoing screening colonoscopies between January 2015 and June 2017. The study analyzed data using methods from previous studies that have demonstrated significant associations between endoscopist characteristics and ADR or pSSPDR. Multilevel mixed-effects logistic regression was performed to examine 7 endoscopist characteristics associated with ADRs and pSSPDRs after controlling for patient demographic, clinical, and colonoscopy-associated factors.ExposuresSeven characteristics of endoscopists performing colonoscopy.Main outcomes and measuresThe ADR and pSSPDR, with a hypothesis created after data collection began.ResultsA total of 16 089 colonoscopies were performed in 16 089 patients by 56 clinicians. Of these, 8339 patients were male (51.8%), and the median (range) age of the cohort was 59 (52-66) years. Analyzing the data by the methods used in 4 previous studies yielded an association between endoscopist and polyp detection; surgeons (OR, 0.49 [95% CI, 0.28-0.83]) and nongastroenterologists (OR, 0.50 [95% CI 0.29-0.85]) had reduced odds of pSSPDR, which was similar to results in previous studies. In a multilevel mixed-effects logistic regression analysis, ADR was not significantly associated with any endoscopist characteristic, and pSSPDR was only associated with years in practice (odds ratio, 0.86 [95% CI, 0.83-0.89] per increment of 10 years; P < .001) and number of annual colonoscopies performed (odds ratio, 1.05 [95% CI, 1.01-1.09] per 50 colonoscopies/year; P = .02).Conclusions and relevanceThe differences in ADRs that were associated with 7 of 7 endoscopist characteristics and differences in pSSPDRs that were associated with 5 of 7 endoscopist characteristics in previous studies may have been associated with residual confounding, because they were not replicated in this analysis. Therefore, these characteristics should not influence the choice of endoscopist for colorectal cancer screening. However, clinicians further from their training and those with lower colonoscopy volumes have lower adjusted pSSPDRs and may need additional training to help increase pSSPDRs.

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.

Dataset Information

CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps.

Publications

CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps.

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