scholarly journals Colorectal Adenocarcinoma with an Alternative Serrated Pathway

2018 ◽  
Vol 12 (1) ◽  
pp. 116-124 ◽  
Author(s):  
Makoto Eizuka ◽  
Keisuke Kawasaki ◽  
Yosuke Toya ◽  
Risaburo Akasaka ◽  
Koki Otsuka ◽  
...  
Keyword(s):  
Colorectal Adenocarcinoma ◽  
Cpg Island ◽  
Genetic Alterations ◽  
High Grade ◽  
Cpg Island Methylator Phenotype ◽  
Serrated Adenoma ◽  
Mlh1 Gene ◽  
Serrated Pathway ◽  
Elevated Lesion ◽  
Methylator Phenotype

In a 64-year-old woman, we identified a flat, elevated lesion that was located at the caecum and was composed of 3 different areas (areas A, B, and C). We diagnosed it as “carcinoma with sessile serrated adenoma/polyp (SSA/P)” histologically. Although area A was diagnosed as classical SSA/P, area B was regarded as a high-grade SSA/P. In contrast, area C showed a differentiated-type adenocarcinoma that invaded the submucosa. The patient had a recurrence of cancer 1.5 years after endoscopic resection. Overexpression of TP53 was detected in area C. Although BRAF mutation was detected in all areas, CpG island methylator phenotype-high cancer was found only in area C. The genomic phenotype of the cancerous tissue was classified as microsatellite stable (MLH1 gene not methylated). In the present case, we showed that a lesion with genetic alterations based on the histological sequence SSA/P → high-grade SSA/P → cancer in SSA/P and an alternative serrated pathway may exhibit aggressive behavior.

scholarly journals P.051 5-hydroxymethylcytosine profiling identifies differential targeting in IDH1 mutant versus IDH1 wild-type high-grade gliomas

2018 ◽  
Vol 45 (s2) ◽  
pp. S29-S29
Author(s):  
W Glowacka ◽  
H Jain ◽  
M Okura ◽  
A Maimaitiming ◽  
R Nejad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Cpg Island ◽  
High Grade ◽  
Spearman Correlation ◽  
Wild Type ◽  
Cpg Island Methylator Phenotype ◽  
B Values ◽  
Active Demethylation ◽  
Methylator Phenotype

Background: Gliomas demonstrate epigenetic dysregulation highlighted by the Glioma CpG-Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. IDH1 mutation perturbs the balance between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) by inhibiting TET-mediated active demethylation. The role 5hmC plays in IDH1 mutant tumors remains poorly understood. Methods: We profiled 5hmC in high grade IDH1 mutant (n = 12) and wild-type (n = 9) tumors on the Illumina MethylationEPIC Beadchip. We examined regions with high 5hmC abundance (top 1% probes), and differentially hydroxymethylated regions (DHMR). 5hmC profiles were correlated with gene expression. Results: Mean 5hmC b-values were 4.6%% and 3.8% for IDH1 mutant and wild-type tumors, respectively. Top 1% and DHMR probes demonstrated increased 5hmC among IDH1 mutants. 5hmC enriched for enhancer and super-enhancers. Among G-CIMP target genes, 22/50 were hydroxymethylated in our IDH1 mutant cohort, suggesting that 5hmC contributes to their overall methylation. Gene expression was associated with gene body 5hmC. 48 genes differentially expressed between IDH1 cohorts showed a positive Spearman correlation between 5hmC and gene expression, in particular for genes upregulated in IDH1 mutants. Conclusions: Locus-specific gain of 5hmC, targeting regulatory regions and associated with over-expressed genes, suggests a significant role for 5hmC in IDH1 mutant HGG.

scholarly journals The CpG island methylator phenotype increases the risk of high-grade squamous intraepithelial lesions and cervical cancer

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Jaqueline Loaeza-Loaeza ◽  
Berenice Illades-Aguiar ◽  
Oscar del Moral-Hernández ◽  
Yaneth Castro-Coronel ◽  
Marco A. Leyva-Vázquez ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Methylation ◽  
Cpg Island ◽  
Hpv Infection ◽  
Low Grade ◽  
High Grade ◽  
Squamous Intraepithelial Lesions ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Intraepithelial Lesions

Abstract Background High-risk human papillomavirus (HR-HPV) infection is the main cause of cervical cancer, but additional alterations are necessary for its development. Abnormal DNA methylation has an important role in the origin and dissemination of cervical cancer and other human tumors. In this work, we analyzed the methylation of eight genes (AJAP1, CDH1, CDH13, MAGI2, MGMT, MYOD1, RASSF1A and SOX17) that participate in several biological processes for the maintenance of cell normality. We analyzed DNA methylation by methylation-specific PCR (MSP) and HPV infection using the INNO‑LiPA genotyping kit in 59 samples diagnostic of normal cervical tissue (non-SIL), 107 low-grade squamous intraepithelial lesions (LSILs), 29 high-grade squamous intraepithelial lesions (HSILs) and 51 cervical cancers (CCs). Results We found that all samples of LSIL, HSIL, and CC were HPV-positive, and the genotypes with higher frequencies were 16, 18, 51 and 56. In general, the genes analyzed displayed a significant tendency toward an increase in methylation levels according to increasing cervical lesion severity, except for the CDH13 gene. High CpG island methylator phenotype (CIMP) was associated with a 50.6-fold (95% CI 4.72–2267.3)-increased risk of HSIL and a 122-fold risk of CC (95% CI 10.04–5349.7). Conclusions We found that CIMP high was significantly associated with HSIL and CC risk. These results could indicate that CIMP together with HR-HPV infection and other factors participates in the development of HSIL and CC.

Serrated and Non-Serrated Precursor Lesions of Colorectal Cancer

2014 ◽  
Vol 33 (1) ◽  
pp. 28-37 ◽  
Author(s):  
Cord Langner
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Aberrant Crypt Foci ◽  
Neoplastic Progression ◽  
Precursor Lesions ◽  
Adenomatous Polyposis ◽  
Cpg Island Methylator Phenotype ◽  
Serrated Adenoma ◽  
Serrated Lesions ◽  
Methylator Phenotype

Although often viewed as a single disease, colorectal cancer more accurately represents a family of diseases with different precursor lesions. Conventional (tubular, tubulovillous and villous) adenomas are the most common neoplastic lesions occurring in the large intestine. They have adenomatous polyposis coli (APC) mutations and arise from dysplastic aberrant crypt foci, initially as polyclonal lesions. In sporadic tumours, neoplastic progression follows the traditional pathway (chromosomal instability pathway), resulting in CpG island methylator phenotype (CIMP)-negative, microsatellite-stable (MSS), BRAF and KRAS wild-type cancers. Germline mutations in the APC gene lead to familial adenomatous polyposis. Conventional adenomas are also the precursors of Lynch syndrome-associated microsatellite-instable (MSI-high) cancers. Sessile serrated adenoma/polyp (SSA/P) is the principal precursor lesion of the serrated pathway, in which BRAF mutation can lead to colorectal cancer with MSI-high CIMP-high or MSS CIMP-high phenotype. SSA/Ps have been associated with synchronous and metachronous invasive adenocarcinomas as well as so-called interval carcinomas. Serrated polyposis is rare but most likely underdiagnosed. Affected individuals bear an increased but unspecified risk for the development of colorectal cancer; close endoscopic surveillance is warranted. Traditional serrated adenomas (TSAs) are much less common than the other serrated lesions. Cancers originating from TSAs may show KRAS mutation with a CIMP-high MSS phenotype.

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 The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status

2010 ◽  
Vol 16 (6) ◽  
pp. 1845-1855 ◽  
Author(s):  
Anna M. Dahlin ◽  
Richard Palmqvist ◽  
Maria L. Henriksson ◽  
Maria Jacobsson ◽  
Vincy Eklöf ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Cpg Island ◽  
Cancer Prognosis ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype

scholarly journals Effects of Somatic Methylation in Colonic Polyps on Risk of Developing Metachronous Advanced Colorectal Lesions

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 246
Author(s):  
Oscar Murcia ◽  
Alejandro Martínez-Roca ◽  
Miriam Juárez ◽  
Mar Giner-Calabuig ◽  
Miren Alustiza ◽  
...  
Keyword(s):  
Cpg Island ◽  
Risk Estimation ◽  
Colonic Polyps ◽  
Cpg Island Methylator Phenotype ◽  
Polyp Size ◽  
Serrated Lesions ◽  
Amplification Technique ◽  
Methylator Phenotype ◽  
The Relationship ◽  
Dependent Probe

The utility of molecular markers for predicting the risk of metachronous advanced colorectal lesions (MACLs) remains poorly investigated. We examined the relationship between somatic hypermethylation in polyps at baseline and the risk of developing MACL. This retrospective cohort study included 281 consecutive patients with colonic polyps who were enrolled between 2007 and 2009 and followed-up until 2014. MACLs were defined as adenomas of >10 mm, high-grade dysplasia, or with a villous component; and serrated lesions of >10 mm or with dysplasia. In total, 595 polyps were removed at baseline colonoscopy and analyzed for pathological characteristics and CpG island methylator phenotype (CIMP) using the MS-MLPA (Methylation-Specific -- Multiplex Ligation-dependent Probe Amplification) technique. Forty-five patients (16.0%) showed at least one CIMP+ polyp. MACL risk was higher in patients with CIMP+ polyps (odds ratio (OR), 4.50; 95% CI, 1.78–11.4; p = 0.002). Patients with CIMP+ polyps also exhibited shorter time to MACL development (33.8 months vs. 50.1 months; p < 0.001), even with adjustment for polyp size and number (OR, 2.40; 95% CI, 1.33–4.34). Adding CIMP analysis improved the sensitivity (57.0% to 70.9%), negative predictive value (71.1% to 77.3%), and overall accuracy (49.8% to 52.0%) for MACL risk estimation. These results highlight that CIMP may be a useful marker for endoscopic surveillance.

scholarly journals Expression and regulatory roles of lncRNAs in G-CIMP-low vs G-CIMP-high Glioma: an in-silico analysis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Indrani Datta ◽  
Houtan Noushmehr ◽  
Chaya Brodie ◽  
Laila M. Poisson
Keyword(s):  
Cpg Island ◽  
Rank Order ◽  
In Silico Analysis ◽  
Good Prognosis ◽  
Cpg Island Methylator Phenotype ◽  
Functional Interpretation ◽  
Protein Coding ◽  
Upstream Regulator ◽  
Methylator Phenotype ◽  
Molecular Relationships

Abstract Background Clinically relevant glioma subtypes, such as the glioma-CpG island methylator phenotype (G-CIMP), have been defined by epigenetics. In this study, the role of long non-coding RNAs in association with the poor-prognosis G-CMIP-low phenotype and the good-prognosis G-CMIP-high phenotype was investigated. Functional associations of lncRNAs with mRNAs and miRNAs were examined to hypothesize influencing factors of the aggressive phenotype. Methods RNA-seq data on 250 samples from TCGA’s Pan-Glioma study, quantified for lncRNA and mRNAs (GENCODE v28), were analyzed for differential expression between G-CIMP-low and G-CIMP-high phenotypes. Functional interpretation of the differential lncRNAs was performed by Ingenuity Pathway Analysis. Spearman rank order correlation estimates between lncRNA, miRNA, and mRNA nominated differential lncRNA with a likely miRNA sponge function. Results We identified 4371 differentially expressed features (mRNA = 3705; lncRNA = 666; FDR ≤ 5%). From these, the protein-coding gene TP53 was identified as an upstream regulator of differential lncRNAs PANDAR and PVT1 (p = 0.0237) and enrichment was detected in the “development of carcinoma” (p = 0.0176). Two lncRNAs (HCG11, PART1) were positively correlated with 342 mRNAs, and their correlation estimates diminish after adjusting for either of the target miRNAs: hsa-miR-490-3p, hsa-miR-129-5p. This suggests a likely sponge function for HCG11 and PART1. Conclusions These findings identify differential lncRNAs with oncogenic features that are associated with G-CIMP phenotypes. Further investigation with controlled experiments is needed to confirm the molecular relationships.

scholarly journals CpG Island Methylator Phenotype-Low (CIMP-Low) in Colorectal Cancer: Possible Associations with Male Sex and KRAS Mutations

2006 ◽  
Vol 8 (5) ◽  
pp. 582-588 ◽  
Author(s):  
Shuji Ogino ◽  
Takako Kawasaki ◽  
Gregory J. Kirkner ◽  
Massimo Loda ◽  
Charles S. Fuchs
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Kras Mutations ◽  
Male Sex ◽  
Methylator Phenotype
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