Intermediate- and low-methylation epigenotypes do not correspond to CpG island methylator phenotype (low and -zero) in colorectal cancer.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE37740 | GEO | 2013/03/08
SECONDARY ACCESSION(S): PRJNA163107
REPOSITORIES: GEO
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Project description:We performed comprehensive genome-scale DNA methylation profiling by Illumina Infinium HumanMethylation27 of 18 DNA pools that represent 84 colorectal cancer (CRC) samples divided according to their high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively) and 3 pools representing 70 normal-adjacent colonic tissues. Bisulphite converted DNA from the 21 DNA pools were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2013-03-08 | E-GEOD-37740 | biostudies-arrayexpress
Project description:PurposeAberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers.Experimental designWe determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays.ResultsThe identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively).ConclusionCIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.
| S-EPMC3268558 | biostudies-literature
Project description:The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation seems to be a distinct epigenotype of colorectal cancer. However, no study has comprehensively examined features of colorectal cancer with less extensive promoter methylation (designated as "CIMP-low"). Using real-time polymerase chain reaction (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1] in 840 relatively unbiased, population-based colorectal cancer samples, obtained from two large prospective cohort studies. CIMP-low (defined as 1/5 to 3/5 methylated promoters) colorectal cancers were significantly more common among men (38 versus 30% in women, P = 0.01) and among KRAS-mutated tumors (44 versus 30% in KRAS/BRAF wild-type tumors, P = 0.0003; 19% in BRAF-mutated tumors, P < 0.0001). In addition, KRAS mutations were significantly more common in CIMP-low tumors (47%) than in CIMP-high tumors (with > or =4/5 methylated promoters, 12%, P < 0.0001) and CIMP-0 tumors (with 0/5 methylated promoters, 37%, P = 0.007). The associations of CIMP-low tumors with male sex and KRAS mutations still existed after tumors were stratified by microsatellite instability status. In conclusion, CIMP-low colorectal cancer is associated with male sex and KRAS mutations. The hypothesis that CIMP-low tumors are different from CIMP-high and CIMP-0 tumors needs to be tested further.
| S-EPMC1876166 | biostudies-literature
Project description:The CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues. In the present study, we investigated whether CIMP+ was associated with a specific mRNA expression pattern for folate- and nucleotide-metabolising enzymes. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RT-PCR. CIMP+ was determined by real-time methylation-specific PCR and compared to mRNA expression. Candidate genes showing association with CIMP+ were further investigated in a replication cohort of 150 CRC samples from Japan. In the exploratory study, low expression of gamma-glutamyl hydrolase (GGH) was strongly associated with CIMP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC. Promoter hypermethylation of GGH was observed in only 5.6% (1 out of 18) CIMP+ tumours and could not account for the low expression level of this gene. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype. Further studies of folate metabolism in CIMP+ CRC may help to elucidate the aetiology of these tumours and to predict their response to anti-folates and 5-fluorouracil/leucovorin.
| S-EPMC2391094 | biostudies-literature
Project description: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.
| S-EPMC8308094 | biostudies-literature
Project description:The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression.The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARbeta2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n=122) was assessed.Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma.These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.
| S-EPMC2703821 | biostudies-literature
Project description:With the aging of the population, the incidence of colorectal cancer in China is increasing. One of the epigenetic alterations: CpG island methylator phenotype (CIMP) plays an important role in the incidence of colorectal cancer. Recent studies have shown that CIMP is closely related to some specific clinicopathological phenotypes and multiple molecular phenotypes in colorectal cancer. In this paper, the newest progress of CIMP colorectal cancer in chemotherapeutic drugs, targeted agents and small molecular methylation inhibitors are going to be introduced. We hope to provide potential clinical treatment strategies for personalized and precise treatment of colorectal cancer patients.
| S-EPMC7952756 | biostudies-literature
Project description:We analyzed 28 fresh frozen samples from pure SCLC patients and 13 noncancerous lung tissues, using the Illumina Infinium 27k Human DNA methylation Beadchip v1.2 Background: Small cell lung cancer (SCLC) accounts for 13-15% of new lung cancer cases in worldwide and has the poor therapeutic outcomes with a median survival of just over one year. A CpG island methylate phenotype (CIMP) is well known as a methylator phenotype with characteristic promoter DNA methylation alterations, in colorectal cancers, glioblastoma and breast cancers, although there has been no report about any CIMP of SCLC. We investigated whether DNA methylation profiles can provide useful molecular subtyping of SCLC in terms of etiology and prognosis of SCLC. Results: We selected a total of 1741 most differentially methylated CpG sites (s.d. > 0.20) across the 28 SCLC tumor tissues in each DNA methylation platform, after an elimination of the probes related with the X- and Y- chromosome. Unsupervised hierarchical clustering of methylation data from SCLC samples reveals two major subgroups with different prognosis: the 5 years disease-free interval (DFI) rate of patients in cluster 1 (11.1%) was lower than that of patients in cluster 2 (61.57%) (p = 0.001). By multivariate analysis for DFI, both postoperative chemotherapy and cluster 1 were a significant prognostic factor (p = 0.002 and 0.002; respectively). Next, among 1220 genes with methylation and expression data both available, the CpG sites were ranked on the basis of the spearman’s correlation coefficient between cluster 1 and cluster 2 into an ascending order. Finally, we identified that fifty-five CpG sites were nagetively correlated and found that apoptosis pathway was a most differentially expressed. Conclusion: By comprehensive DNA methylation profiling, two distinct subgroups with different molecular and clinical phenotype were identified to evoke a CIMP of SCLC. We found some promoter markers in the apoptosis pathway could make a difference between the two groups, and we hope that our data can contribute to provide a useful resource for the construction of therapeutic strategy and the development of a new chemotherapeutic agent. After genomic DNA was treated with sodium bisulfite, bisulfite-converted genomic DNA was analyzed using Illumina’s Infinium HumanMethylation27 BeadChip.
2013-08-29 | E-GEOD-50412 | biostudies-arrayexpress
Project description:Background Gastric cancer (GC) was characterized by unique DNA methylation epigenotypes (MEs). Still, MEs, including adenocarcinoma of the esophagogastric junction (AEG) and background non-neoplastic columnar mucosae (NM), are yet to be clarified. Methods We analyzed genome-wide DNA MEs of AEG, GC, and background NM using Infinium 450k beadarray, followed by quantitative pyrosequencing validation. Large-scale data of the Cancer Genome Atlas (TCGA) were additionally reviewed. Results Unsupervised two-way hierarchical clustering using Infinium data of 21 AEG, 30 GC, and 11 NM showed four DNA MEs: extremely high-ME (E-HME), high-ME (HME), low-ME (LME), and extremely low-ME (E-LME). The promoter methylation levels were validated by pyrosequencing in 146 samples. Although almost normal mucosae were clustered into E-LME, gastric or esophagogastric junction mucosae with chronic inflammatory change due to either Helicobacter pylori infection or reflux esophagitis were clustered together into LME, which suggested that the inflammation status determined DNA MEs regardless of the causes. Three cases of Barrett’s-related adenocarcinoma were all clustered into HME. Among 94 patients whose tumors can be clustered into one of four MEs, 11 patients with E-LME cancers showed significantly shorter overall survival than the other MEs, even in multivariate Cox regression estimate. TCGA data also showed enrichment of AEG in HME and a poorer prognosis of E-LME. Conclusions E-LME cases, newly confirmed in this study, would be a unique aggressive subtype not associated with the elevation of DNA methylation levels caused by inflammation. LME could be acquired via chronic inflammation independent of the causes, and AEG frequently showed HME.
2022-10-20 | GSE207846 | GEO
Project description:A subset of colorectal cancers was postulated to have the CpG island methylator phenotype (CIMP), a higher propensity for CpG island DNA methylation. The validity of CIMP, its molecular basis, and its prognostic value remain highly controversial. Using MBD-isolated genome sequencing, we mapped and compared genome-wide DNA methylation profiles of normal, non-CIMP, and CIMP colon specimens. Multidimensional scaling analysis revealed that each specimen could be clearly classified as normal, non-CIMP, and CIMP, thus signifying that these three groups have distinctly different global methylation patterns. We discovered 3780 sites in various genomic contexts that were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal colon. An additional 2026 sites were found to be hypermethylated in CIMP tumors only; and importantly, 80% of these sites were located in CpG islands. These data demonstrate on a genome-wide level that the additional hypermethylation seen in CIMP tumors occurs almost exclusively at CpG islands and support definitively that these tumors were appropriately named. When these sites were examined more closely, we found that 25% were adjacent to sites that were also hypermethylated in non-CIMP tumors. Thus, CIMP is also characterized by more extensive methylation of sites that are already prone to be hypermethylated in colon cancer. These observations indicate that CIMP tumors have specific defects in controlling both DNA methylation seeding and spreading and serve as an important first step in delineating molecular mechanisms that control these processes.
| S-EPMC3266035 | biostudies-literature