scholarly journals The proto CpG island methylator phenotype of sessile serrated adenomas/polyps

2018 ◽  
Author(s):  
Hannah R. Parker ◽  
Stephany Orjuela ◽  
Andreia Martinho Oliveira ◽  
Fabrizio Cereatti ◽  
Matthias Sauter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cpg Island ◽  
Cpg Islands ◽  
Normal Mucosa ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Colon Cancers ◽  
Methylator Phenotype ◽  
Serrated Adenomas

AbstractSessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ˜20% of colon cancers with the CpG island methylator phenotype (CIMP), but their molecular features are poorly understood. We used high-throughput analysis of DNA methylation and gene expression to investigate the epigenetic phenotype of SSA/Ps. Fresh-tissue samples of 17 SSA/Ps and (for comparison purposes) 15 conventional adenomas (cADNs)—each with a matched sample of normal mucosa— were prospectively collected during colonoscopy (total no. samples analyzed: 64). DNA and RNA were extracted from each sample. DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ˜2.7 million CpG sites located predominantly in gene regulatory regions and spanning 80.5Mb (˜2.5% of the genome); RNA was sequenced to define the samples’ transcriptomes. An independent series of 61 archival lesions was used for targeted verification of DNA methylation findings. Compared with normal mucosa samples, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps’ putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions (3 SSA/P-specific and 3 common) demonstrated the high potential of DNA methylation markers for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression (n=618 genes vs 349 that were downregulated); downregulation was more common in cADNs (n=712 vs 516 upregulated genes). The epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers that can add precision to the clinical management of the two most frequent colon-cancer precursors.

Potential tumor suppressor miR-1247 is down-regulated in CpG island methylator phenotype colon cancers

2012 ◽  
Vol 215 (3) ◽  
pp. S11
Author(s):  
Jennifer J. Liang ◽  
Kathryn L. DeJulius ◽  
Awad Jarrar ◽  
Angela Ting ◽  
James Church ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Colon Cancers ◽  
Methylator Phenotype ◽  
Potential Tumor Suppressor

scholarly journals The proto CpG island methylator phenotype of sessile serrated adenomas/polyps

Epigenetics ◽  
2018 ◽  
Vol 13 (10-11) ◽  
pp. 1088-1105 ◽  
Author(s):  
Hannah R. Parker ◽  
Stephany Orjuela ◽  
Andreia Martinho Oliveira ◽  
Fabrizio Cereatti ◽  
Matthias Sauter ◽  
...  
Keyword(s):  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Serrated Adenomas

scholarly journals How theBRAFV600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Catherine E. Bond ◽  
Vicki L. J. Whitehall
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Early Event ◽  
Sporadic Colorectal Cancer ◽  
Cpg Island Methylator Phenotype ◽  
Distinct Subgroup ◽  
Molecular Features ◽  
Map Kinase Pathway ◽  
Methylator Phenotype ◽  
Kinase Pathway

TheBRAFoncogene is an integral component of the MAP kinase pathway, and an activating V600E mutation occurs in 15% of sporadic colorectal cancer. This is an early event in serrated pathway tumourigenesis, and theBRAFV600E has been commonly associated with the CpG island methylator phenotype, microsatellite instability (MSI), and a consistent clinical presentation including a proximal location and predilection for elderly females. A proportion of theBRAFmutant lesions remain as microsatellite stable (MSS), and in contrast to the MSI cancers, they have an aggressive phenotype and correlate with poor patient outcomes. Recent studies have found that they have clinical and molecular features of both theBRAFmutant/MSI and the conventionalBRAFwild-type cancers and comprise a distinct colorectal cancer subgroup. This review highlights the importance of theBRAFmutation occurring in colorectal cancer stratified for molecular background and discusses its prognostic and clinical significance.

Epigenetic Dysregulation of Candidate Cis-Regulatory Sequences in Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2229-2229
Author(s):  
Reid F. Thompson ◽  
Maria E. Figueroa ◽  
Ari M. Melnick ◽  
John M. Greally
Keyword(s):  
Cytosine Methylation ◽  
Hematological Malignancies ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Regulatory Sequences ◽  
Cpg Island Methylator Phenotype ◽  
Global Methylation ◽  
Methylator Phenotype ◽  
Tumor Types

Abstract Epigenetic changes (in particular, altered cytosine methylation) have been described in a variety of tumors. The CpG Island Methylator Phenotype (CIMP) is a well-known instance of this phenomenon wherein cytosine methylation is markedly dysregulated (normally hypomethylated loci shift to a methylated state). CIMP has been demonstrated in a number of different cancer types including hematological malignancies like AML. While methylation status has been studied predominantly at CpG islands, we used a novel assay (HELP; Khulan et al., Genome Res. 2006) to look for changes in cytosine methylation in large contiguous regions of the genome. We assessed global patterns of cytosine methylation by HELP analysis in a variety of tumor samples including leukemias and lymphomas. We found significant changes in the global methylation patterns of malignant cells, confirming prior observations of epigenetic dysregulation in these tumor types. We also discovered that the majority of the changes in cytosine methylation are occurring not at CpG islands but at other loci in the genome, including constitutively hypomethylated loci that we are finding to be candidate cis-regulatory sequences. We conclude that cytosine methylation changes in cancer occur much more extensively than analysis of CpG islands alone would indicate, and that the epigenetic dysregulation in cancer may be predominantly targeted to cis-regulatory sequences rather than to promoters.

CpG Island Methylation Is a Poor Prognostic Factors in Myelodysplastic Syndrome Patients and Is Reversed by Decitabine Therapy-Results of a Phase III Randomized Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 790-790 ◽  
Author(s):  
Lanlan Shen ◽  
Hagop Kantarjian ◽  
Hussain Saba ◽  
E. Lin ◽  
Don Berry ◽  
...  
Keyword(s):  
Supportive Care ◽  
Cpg Island ◽  
Randomized Study ◽  
Cpg Islands ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Multiple Time ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Multiple Time Points

Abstract Background. In human neoplasia, aberrant methylation of CpG islands leads to gene silencing, and has an essential role in tumorigenesis through down regulation of tumor suppressor genes. A phase III randomized study comparing a DNA methyltransferase inhibitor; decitabine (DAC) versus supportive care has been completed recently in myelodysplastic syndrome (MDS) patients. The purpose of our study was to determine the prognostic significance of CpG islands methylation in these patients, to test the significance of methylation events in predicting drug response, and to explore the correlation between modulation of DNA methylation and response to DAC. Methods. DNA was extracted from blood and bone marrow of 89 patients before treatment (baseline) and also from a subset of 34 patients at multiple time-points and modified by bisulfite. In this study, we selected 24 CpG islands based on previous studies and ongoing efforts to identify methylated genes by MCA/RDA. For 14 genes, very low levels of methylation were detected in an initial group of 20 MDS patients, and we excluded them from further study. We then analyzed the methylation status of a total of 10 genes in all the samples. Bisulfite-PCR followed by Pyrosequencing was used to analyze DNA methylation levels of each gene. For statistical analysis, methylation levels of each gene were normalized by a Z score method, and each patient was assigned a methylation “score” based on the sum of Z scores for all genes, or a selected group of genes. Samples before and after treatment were available for 20 patients on supportive care (SC) and 14 patients on DAC, and methylation levles at each time point were averaged across the 10 genes. Results. Methylation frequencies of RIL, PGRA, PGRB, Olig2, p15, CDH13, NPM2, ECAD, NOR1 and ER ranged from 7% to 70% in MDS patients at baseline. Methylation levels of all these genes were significantly linked, suggesting concurrent methylation affected by CpG Island Methylator Phenotype (CIMP). There was no association between methylation by Z scores with age, IPSS, or cytogenetics. There was no correlation between baseline methylation and response to DAC therapy. By univariate analysis, methylation was significantly associated with both shortened overall survival and progression-free survival. In multivariate analysis, IPSS score and methylation were independent predictors of progression free survival, and methylation was the only independent predictor of overall survival. Methylation changes were then analyzed for correlation with response in 34 patients (Decitabine arm: 2 CR, 3 PR, 4HI, 4 SD, 1 PD; supportive care arm: 2 HI, 6 SD, 12 PD) at multiple time-points. At the latest available time-point (>4 months at therapy), methylation decreased by 11.2% in patients in DAC but increased by 20.1% in patients in SC. A greater decrease was observed in patients with CR or PR (40.6+/− 15.7%) compared to HI (9.8+/− 13.2%). Methylation increased by 15.4% in patients with SD and 27.2% in patients with PD. Conclusions. Concordant methylation of multiple genes suggests the existence of a CpG island methylator phenotype in MDS. This methylation was associated with poor prognosis and risk of leukemia transformation. Decitabine therapy was associated with reduced methylation over time, which was associated with clinical responses.

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