CpG Island Methylator Phenotype—A Hope for the Future or a Road to Nowhere?

The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies.

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Four Molecular Subtypes of Colorectal Cancer and Their Precursor Lesions

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0523-ra.1 ◽

2011 ◽

Vol 135 (6) ◽

pp. 698-703

Author(s):

Gyeong Hoon Kang

Keyword(s):

Molecular Subtypes ◽

Cpg Island ◽

Colorectal Carcinogenesis ◽

Colorectal Cancers ◽

Precursor Lesions ◽

Cpg Island Methylator Phenotype ◽

Molecular Features ◽

Epigenetic Instability ◽

Geographic Differences ◽

Methylator Phenotype

Abstract Context.—In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI−, CIMP−/MSI+, and CIMP−/MSI−. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. Objective.—To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. Data Sources.—This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). Conclusion.—The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.

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Are clinicopathological features of colorectal cancers with methylation in half of CPG island methylator phenotype panel markers different from those of CPG island methylator phenotype-high colorectal cancers?

Pathology ◽

10.1016/j.pathol.2015.12.418 ◽

2016 ◽

Vol 48 ◽

pp. S153

Author(s):

Ye-Young Rhee ◽

Jeong-Mo Bae ◽

Kyung-Ju Kim ◽

Xianyu Wen ◽

Young-Seok Song ◽

...

Keyword(s):

Cpg Island ◽

Clinicopathological Features ◽

Colorectal Cancers ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-08-0091 ◽

2008 ◽

Vol 17 (7) ◽

pp. 1774-1780 ◽

Cited By ~ 75

Author(s):

Dallas R. English ◽

Joanne P. Young ◽

Julie A. Simpson ◽

Mark A. Jenkins ◽

Melissa C. Southey ◽

...

Keyword(s):

Cpg Island ◽

Braf V600e Mutation ◽

Braf V600e ◽

Colorectal Cancers ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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

Blood ◽

10.1182/blood.v108.11.2229.2229 ◽

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.

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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 ◽

10.1182/blood.v106.11.790.790 ◽

2005 ◽

Vol 106 (11) ◽

pp. 790-790 ◽

Cited By ~ 3

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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745 Colorectal Cancers (CRCs) With the CpG Island Methylator Phenotype (CIMP) Do Not Show Improved Survival With 5-Fluorouracil (5FU)-Based Adjuvant Chemotherapy

Gastroenterology ◽

10.1016/s0016-5085(10)60466-0 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-102

Author(s):

Rodrigo Jover ◽

Thuy-Phuong T. Nguyen ◽

Lucía Pérez-Carbonell ◽

Artemio Payá ◽

Cristina Alenda ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Cpg Island ◽

Colorectal Cancers ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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CpG Island Methylator Phenotype in Colorectal Cancers: Comparison of the New and Classic CpG Island Methylator Phenotype Marker Panels

Archives of Pathology & Laboratory Medicine ◽

10.5858/2008-132-1657-cimpic ◽

2008 ◽

Vol 132 (10) ◽

pp. 1657-1665 ◽

Cited By ~ 1

Author(s):

Sun Lee ◽

Nam-Yun Cho ◽

Eun Joo Yoo ◽

Jung Ho Kim ◽

Gyeong Hoon Kang

Keyword(s):

Clinical Outcome ◽

Microsatellite Instability ◽

Braf Mutation ◽

Cpg Island ◽

Tumor Location ◽

Colorectal Cancers ◽

Clinicopathologic Features ◽

Cpg Island Methylator Phenotype ◽

P Values ◽

Methylator Phenotype

Abstract Context.—CpG island methylator phenotype (CIMP) designates a subset of colorectal cancers featuring concordant hypermethylation of multiple promoter CpG islands. Little is known about the clinical outcome or histologic characteristics of CIMP-positive colorectal cancers defined by recently identified CpG island methylator phenotype panels. Objective.—To investigate and compare the molecular and clinicopathologic features of CIMP-positive colorectal cancers defined by classic (p16, hMLH1, MINT1, MINT2, MINT31) and new (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1) CIMP panels. Design.—We analyzed 130 colorectal cancers for hypermethylation of both panels using methylation-specific polymerase chain reaction. Results.—With at least 2 markers methylated, both classic (39/130; 23.1%) and new (23.1%) CIMP-positive colorectal cancers were significantly associated with proximal tumor location, microsatellite instability, and BRAF mutation (all P values were less than .05). The new panel outperformed the classic panel in detecting these features. With at least 3 markers methylated, new CIMP-positive colorectal cancers (16.9%) were closely associated with proximal tumor location, low frequency of KRAS mutation, and high frequency of BRAF mutation (all P values were less than .05), whereas classic CIMP-positive colorectal cancers (18.5%) were closely associated with proximal tumor location, frequent microsatellite instability, and frequent BRAF mutation (all P values were less than .05). Analyzing a combination of CIMP and microsatellite instability status, CIMP-positive/microsatellite instability–negative colorectal cancers had the worst clinical outcomes. Conclusions.—Whereas the classic panel outperformed in predicting clinical outcome, the new panel was superior in detecting known clinicopathologic features of CIMP but inferior in prognostication power.

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