Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status

Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods: LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori-related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori-related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.

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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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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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The Methylation of SDC2 and TFPI2 Defined Three Methylator Phenotypes of Colorectal Cancer

10.21203/rs.3.rs-1022929/v1 ◽

2021 ◽

Author(s):

Ruixue Lei ◽

Yanteng Zhao ◽

Kai Huang ◽

Qian Wang ◽

Kangkang Wan ◽

...

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Methylation Status ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Tumor Location ◽

Functional Enrichment ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype ◽

Almost All

Abstract BackgroudMethylated SDC2 and TFPI2 are applied frequently for the early detection of colorectal cancer (CRC). However, they often miss some positive samples, which directly affects their sensitivities, and the underlining mechanism is not well known.Methods:CRC samples from TCGA and GEO datasets were divided into three groups, Highmethylation/ High-methylation (HH), High-methylation/Low-methylation (HL), and Lowmethylation/Low-methylation (LL) according to the methylation status of SDC2 and TFPI2 promoters. Variations in age, tumor location, and microsatellite instable were then assessed between the three groups and verified in our custom cohort.ResultsSamples of HL group preferred to derive from left-sided CRCs (P < 0.05). HH samples showed the highest microsatellite instability and mutation load (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02, P = 0.0055). Almost all mutations of BRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were observed in HH group (HH/HL/LL: 51/0/1, P = 0.018). Besides, older patients were frequently found in HH group. Expression analysis identified 37, 84, and 22 group-specific differentially expressed genes (DEGs) for HH, HL, and LL, respectively. Functional enrichment analysis revealed that HH-specific DEGs were mainly related to transcription regulation, while LL-specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration.Conclusions:The three methylation phenotypes identified based on SDC2 and TFPI2 methylation status showed extensive variations in tumor location, patient age, MSI and ECM biology processes, suggesting that these respective sides should be considered when developing new methylation-based biomarkers for CRC detection.

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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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