Project description:Cancer-specific changes in DNA methylation can alter genetic stability, genomic structure, and gene expression. Promoter CpG island methylation can result in transcriptional silencing and plays an important role in the oncogenic process. We used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Here, we describe the identification of novel groups of breast tumors characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating the existence of a breast-CpG island methylator phenotype (B-CIMP). B-CIMP imparts a distinct epigenomic profile and is a strong determinant of metastatic potential.
Project description:Methylation is closely involved in the development of various carcinomas. However, little datasets are available for small cell lung carcinoma (SCLC) due to the scarcity of fresh tumor samples. The aim of this study is to investigate the comprehensive genome-wide methylation profile of SCLC to predict the prognosis after surgical treatment. We investigated the high DNA methylated and low gene expression sites using 25 SCLC tumor tissues. First, we selected most differentially methylated CpG sites across the tumor tissues. Following hierarchical clustering (HC) and non-negative matrix factorization (NMF), gene ontology analysis was performed using DAVID software. Clustering of SCLC tumors led to the important identification of a CpG island methylator phenotype (CIMP) of SCLC, and showed that CIMP-high tumors had a significantly poorer prognosis (p = 0.001). Multivariate analysis revealed that postoperative chemotherapy, low neuroendocrine expression and the CIMP-low state were significantly good prognostic factors. Association analyses of methylation and gene expression provided 46 genes with significant correlation. Ontology studies to these genes showed that genes involved in extrinsic apoptosis pathway were suppressed, including TNFRSF1A, TNFRSF10A and TRADD, in CIMP-high tumors, prognosis of which was poorer. By comprehensive DNA methylation profiling, two distinct subgroups were identified to evoke a CIMP of SCLC as a useful marker for determination of treatment. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for the treatment of an aggressive subtype of SCLC. Comprehensive genome-wide methylation analyses
Project description:Cancer-specific changes in DNA methylation can alter genetic stability, genomic structure, and gene expression. Promoter CpG island methylation can result in transcriptional silencing and plays an important role in the oncogenic process. We used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Here, we describe the identification of novel groups of breast tumors characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating the existence of a breast-CpG island methylator phenotype (B-CIMP). B-CIMP imparts a distinct epigenomic profile and is a strong determinant of metastatic potential. Gene Expression Samples (GSM647057-GSM647077): Twenty-one breast cancer primary samples were analyzed. There are 10 CIMP positive and 11 CIMP negative samples. Methylation Profiling Samples (GSM651372-GSM651410): Thirty-nine breast cancer primary samples were analyzed. There are 17 CIMP positive and 22 CIMP negative samples.
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.
Project description:The CpG island methylator phenotype is common in both BRAF mutant colorectal cancer and their precursors, the sessile serrated adenoma (SSA). SSAs acquire dysplasia immediate prior to progressing to invasive cancer. Here we examine the methylome of the remnant non-dysplastic portion of dysplastic sessile serrated adenomas to identify changes that occur immediately prior to the development of overt histological dysplasia.
Project description:Methylation is closely involved in the development of various carcinomas. However, little datasets are available for small cell lung carcinoma (SCLC) due to the scarcity of fresh tumor samples. The aim of this study is to investigate the comprehensive genome-wide methylation profile of SCLC to predict the prognosis after surgical treatment. We investigated the high DNA methylated and low gene expression sites using 25 SCLC tumor tissues. First, we selected most differentially methylated CpG sites across the tumor tissues. Following hierarchical clustering (HC) and non-negative matrix factorization (NMF), gene ontology analysis was performed using DAVID software. Clustering of SCLC tumors led to the important identification of a CpG island methylator phenotype (CIMP) of SCLC, and showed that CIMP-high tumors had a significantly poorer prognosis (p = 0.001). Multivariate analysis revealed that postoperative chemotherapy, low neuroendocrine expression and the CIMP-low state were significantly good prognostic factors. Association analyses of methylation and gene expression provided 46 genes with significant correlation. Ontology studies to these genes showed that genes involved in extrinsic apoptosis pathway were suppressed, including TNFRSF1A, TNFRSF10A and TRADD, in CIMP-high tumors, prognosis of which was poorer. By comprehensive DNA methylation profiling, two distinct subgroups were identified to evoke a CIMP of SCLC as a useful marker for determination of treatment. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for the treatment of an aggressive subtype of SCLC.
Project description:In order to identify other molecular aberrations that may cooperate with IDH1R132MUT in gliomagenesis, we performed CpG-island methylation profiling analysis using MSRE (Tran et al. Front. Neurosci. 3:57. Doi: 10.3389/neuro.15.005.2009) on a subset of IDH1R132MUT and IDH1R132WT GBMs and found a distinct pattern of CpG island hypermethylation that was detected in all GBMs and lower grade gliomas with IDH1R132MUT. While absent from nearly all IDH1R132WT glioma, the methylation pattern in IDH1R132MUT GBMs shows similarity to the recently reported CpG island methylator phenotype (CIMP) found to be tightly associated with IDH1R132MUT gliomas(Noushmehr et al. Cancer Cell, Volume 17, Issue 5, 18 May 2010, Pages 510-522, ISSN 1535-6108, DOI: 10.1016/j.ccr.2010.03.017).