scholarly journals The CIMP Phenotype inBRAFMutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Winnie C. Fernando ◽  
Mariska S. Miranda ◽  
Daniel L. Worthley ◽  
Kazutomo Togashi ◽  
Dianne J. Watters ◽  
...  
Keyword(s):  
Cpg Island ◽  
Strong Association ◽  
Proximal Colon ◽  
Cpg Island Methylator Phenotype ◽  
Serrated Polyps ◽  
Serrated Polyp ◽  
Increased Risk ◽  
Methylator Phenotype ◽  
Serrated Adenomas ◽  
Methylight Assay

Colorectal cancers arising via the serrated pathway are often associated withBRAFV600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association betweenBRAFV600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such asMLH1, p16,andIGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated withBRAFmutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%).MLH1methylation was mainly observed in the proximal colon and was significantly associated withBRAFmutation and CIMP-high. The number of samples methylated forp16andIGFBP7was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes.

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 Clinicopathological and Molecular Profiles of Sporadic Microsatellite Unstable Colorectal Cancer with or without the CpG Island Methylator Phenotype (CIMP)

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3487
Author(s):  
Shih-Ching Chang ◽  
Anna Fen-Yau Li ◽  
Pei-Ching Lin ◽  
Chun-Chi Lin ◽  
Hung-Hsin Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Gene Mutations ◽  
Proximal Colon ◽  
Tnm Stage ◽  
Cpg Island Methylator Phenotype ◽  
Kras Mutations ◽  
Methylator Phenotype ◽  
Next Generation Sequencing Ngs ◽  
Mutation Spectra

Background: The 5’-C-phosphate-G-3’ island methylator phenotype (CIMP) is a specific phenotype of colorectal cancer (CRC) associated with microsatellite instability-high (MSI-high) tumors. Methods: In this study, we determined the CIMP status using eight methylation markers in 92 MSI-high CRC patients after excluding five germline mismatch repair (MMR) gene mutations analyzed by next-generation sequencing (NGS) and confirmed by Sanger sequencing. The mutation spectra of 22 common CRC-associated genes were analyzed by NGS. Results: Of the 92 sporadic MSI-high tumors, 23 (25%) were considered CIMP-high (expressed more than 5 of 8 markers). CIMP-high tumors showed proximal colon preponderance and female predominance. The mutation profiles of CIMP-high tumors were significantly different from those of CIMP-low or CIMP-0 tumors (i.e., higher frequencies of BRAF, POLD1, MSH3, and SMAD4 mutations but lower frequencies of APC, TP53, and KRAS mutations). Multivariate analysis demonstrated that tumor, node, metastasis (TNM) stage was the independent prognostic factor affecting overall survival (OS). Among the MSI-high cases, the CIMP status did not impact the outcome of patients with MSI-high tumors. Conclusions: Only TNM stage was a statistically significant predictor of outcomes independent of CIMP profiles in MSI-high CRC patients. Sporadic MSI-high CRCs with different mechanisms of carcinogenesis have specific mutation profiles and clinicopathological features.

scholarly journals A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps

2014 ◽  
Vol 8 (5) ◽  
pp. 1937-1944 ◽  
Author(s):  
KOJI HOKAZONO ◽  
TAKASHI UEKI ◽  
KINUKO NAGAYOSHI ◽  
YASUNOBU NISHIOKA ◽  
TATSUNOBU HATAE ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Serrated Polyps ◽  
Methylator Phenotype

scholarly journals Association of BMI and major molecular pathological markers of colorectal cancer in men and women

2020 ◽  
Vol 111 (3) ◽  
pp. 562-569
Author(s):  
Prudence R Carr ◽  
Efrat L Amitay ◽  
Lina Jansen ◽  
Elizabeth Alwers ◽  
Wilfried Roth ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Multinomial Logistic Regression ◽  
Population Based ◽  
German Population ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Feature ◽  
Increased Risk ◽  
Methylator Phenotype ◽  
Underlying Mechanisms

ABSTRACT Background Observational studies have consistently shown that a high BMI is associated with increased risk of colorectal cancer (CRC). However, the underlying mechanisms linking obesity to CRC remain unclear. Objectives To investigate the associations of BMI and CRC by major molecular pathological subtypes of CRC. Methods This analysis included 2407 cases and 2454 controls from a large German population–based case–control study. Information on recent weight and height as well as other demographic and lifestyle data were obtained by standardized interviews. Multinomial logistic regression was used to estimate ORs and 95% CIs for the associations between BMI and risk of CRC by major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype (CIMP), B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Results Among women, a higher BMI was differentially and more strongly associated with risk of MSI CRC (OR per 5 kg/m2: 1.69; 95% CI: 1.34, 2.12; Pheterogeneity ≤ 0.001), CIMP-high CRC (OR per 5 kg/m2: 1.57; 95% CI: 1.30, 1.89; Pheterogeneity ≤ 0.001), BRAF-mutated CRC (OR per 5 kg/m2: 1.56; 95% CI: 1.22, 1.99; Pheterogeneity = 0.04), and KRAS-wildtype CRC (OR per 5 kg/m2: 1.35; 95% CI: 1.17, 1.54; Pheterogeneity = 0.01), compared with the risk of CRC in subjects with the molecular feature counterpart. In men, no meaningful differences in CRC risk were observed for the investigated molecular feature pairs. For the association of BMI with MSI CRC, we observed effect modification by sex (Pinteraction = 0.04). Also, in women, the risk of CRC with the serrated pathway features was more strongly increased with higher BMI than risk of CRC with the traditional pathway features (OR per 5 kg/m2: 1.73; 95% CI: 1.28, 2.34; Pheterogeneity = 0.01). Conclusions In women, the relation between BMI and MSI-high CRC seems to be stronger than that between BMI and microsatellite-stable CRC. However, a validation in an independent cohort is needed. This observational study was registered at the German Clinical Trials Register (http://www.drks.de; study ID: DRKS00011793), an approved primary register in the WHO network.

scholarly journals Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3529
Author(s):  
Sabine Meessen ◽  
Nicola Currey ◽  
Zeenat Jahan ◽  
Hannah W. Parker ◽  
Mark A. Jenkins ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Predictive Marker ◽  
Proximal Colon ◽  
Marker Genes ◽  
Colorectal Carcinomas ◽  
Loss Of Function ◽  
Cpg Island Methylator Phenotype ◽  
Tetranucleotide Repeat ◽  
Methylator Phenotype

MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as “elevated microsatellite alterations at selected tetranucleotide repeats” (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.

scholarly journals Traditional serrated adenoma: an overview of pathology and emphasis on molecular pathogenesis

2019 ◽  
Vol 6 (1) ◽  
pp. e000317 ◽  
Author(s):  
Aoife J McCarthy ◽  
Stefano Serra ◽  
Runjan Chetty
Keyword(s):  
Cpg Island ◽  
Molecular Pathogenesis ◽  
Cpg Island Methylator Phenotype ◽  
Serrated Adenoma ◽  
Serrated Polyp ◽  
Molecular Events ◽  
Eosinophilic Cytoplasm ◽  
Small Bowel Mucosa ◽  
Methylator Phenotype ◽  
Molecular Landscape

ObjectiveTo provide an overview of the pathology and molecular pathogenesis of traditional serrated adenomas (TSA).DesignDescribe the morphology and molecules that play a role in their pathogenesis.ResultsThese exuberant polypoid lesions are typified by tall cells with deeply eosinophilic cytoplasm, elongated nuclei bearing delicate chromatin, ectopic crypt foci, deep clefting of the lining mucosa and an overall resemblance to small bowel mucosa.Broadly, TSAs arise via three mechanisms. They may be BRAF mutated and CpG island methylator phenotype (CIMP)-high: right sided, mediated through a microvesicular hyperplastic polyp or a sessile serrated adenoma, may also have RNF43 mutations and result in microsatellite stable (MSS) colorectal cancers (CRC). The second pathway that is mutually exclusive of the first is mediated through KRAS mutation with CIMP-low TSAs. These are left-sided TSAs, are not associated with another serrated polyp and result in MSS CRC. These TSAs also have RSPO3, RNF43 and p53 mutations together with aberrant nuclear localisation of β-catenin. Third, there is a smaller group of TSAs that are BRAF and KRAS wild type and arise by as yet unknown molecular events. All TSAs show retention of mismatch repair proteins.ConclusionThese are characteristic unusual polyps with a complex molecular landscape.

scholarly journals Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location

2020 ◽  
Vol 4 (5) ◽  
Author(s):  
Julia D Labadie ◽  
Tabitha A Harrison ◽  
Barbara Banbury ◽  
Efrat L Amtay ◽  
Sonja Bernd ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Cpg Island ◽  
Distal Colon ◽  
Tumor Location ◽  
Proximal Colon ◽  
Postmenopausal Hormone Therapy ◽  
Cpg Island Methylator Phenotype ◽  
Tumor Subtypes ◽  
Methylator Phenotype

Abstract Background Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors. Conclusions We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

scholarly journals The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1017 ◽  
Author(s):  
Fatima De Palma ◽  
Valeria D’Argenio ◽  
Jonathan Pol ◽  
Guido Kroemer ◽  
Maria Maiuri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Kras Mutations ◽  
Serrated Polyps ◽  
Prognostic Features ◽  
Normal Colon Mucosa ◽  
Serrated Pathway ◽  
Epigenetic Biomarkers ◽  
Serrated Adenomas

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.

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.

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