Mutations in IDH1 and IDH2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Derek Chiang
PROVIDER: E-GEOD-32079 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE32079: Mutations in IDH1 and IDH2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas GSE32283: Mutations in IDH1 are associated with DNA hypermethylation in glioblastomas Refer to individual Series
2012-06-09 | E-GEOD-32286 | biostudies-arrayexpress
Project description:The impact of different carcinogenic exposures on the specific patterns of somatic mutations in human tumors remains unclear. To clarify this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by liver fluke Opisthorchis viverrini (OV)-infection and 101 cases due to non-OV etiologies. Whole-exome (N = 15) and prevalence screening (N = 194) revealed recurrent somatic mutations in BAP1 and ARID1A, neither of which has been previously reported to be mutated in CCA. Comparisons between intrahepatic OV and non-OV CCAs demonstrated statistically significant different mutation patterns: BAP1 and IDH1/2 were more frequently mutated in non-OV CCAs, while TP53 displayed the reciprocal pattern. Functional studies demonstrated tumor suppressive roles of BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations even within the same tumor type. Illumina 450k methylation array profiling performed on wild-type (n=23) and mutant (n=9) CCA (cholangiocarcinoma) samples, with adjacent normal tissue (n=4)
2013-10-20 | E-GEOD-49656 | biostudies-arrayexpress
Project description:TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. Genome wide DNA methylation profiling of patients samples with various myeloid malignancies and diffrential levels of 5hmC.The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in bone marrow samples and occasionally peripheral blood samples. Samples included 28 control healthy bone marrows, 29 patients samples with low 5hmC levels (7 patients with wild-type TET2 and 22 mutant TET2) and 24 with high levels of 5hmC (22 with wild-type TET2 and 2 mutant TET2). Bisulphite converted DNA from 81 samples was hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2010-12-11 | E-GEOD-25706 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of HCT116 WT, HCT116 DNMT1 and DNMT3B double KO, and breast cancer tumors by next generation Infinium assay Bisulfite converted DNA from 22 samples were hybridized to the Illumina's HumanMethylation450 BeadChip
2011-12-15 | E-GEOD-29290 | biostudies-arrayexpress
Project description:Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human ESCs and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1, and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34+ HSPCs and differentiated derivatives from CD34+ HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment. Total DNA isolated by standard procedures from different primary samples corresponding to healthy patients and several cell lines.
2011-09-14 | E-GEOD-30090 | biostudies-arrayexpress
Project description:We report on the molecular and cellular events observed in two patients treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both patients exhibited silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of EVI1. In line with this observation, a genome wide methylation analysis of 807 cancer related genes revealed a DNA methylation pattern characteristic of MDS and AML patients. Genomic DNA was prepared from peripheral blood cells of patient 1 (d 0 and month 27) and 25 healthy controls including 12 males and 13 females. The GoldenGate Methylation Cancer Panel I array was used to compare methylation degree in 1.505 CpG sites from promoter regions or the first exon of 807 mostly cancer related genes between the patient 1 (d 0 and month 27) and 25 healthy controls.
2010-06-24 | E-GEOD-19515 | biostudies-arrayexpress
Project description:Human aging implies many phenotypic modifications and an increased susceptibility to many common diseases, phenomena that cannot be fully explained by the constrained genetic setting. An alternative pathway that could explain the age-associated alterations is epigenetic drifts. To address this issue, we performed Whole Genome Bisulfite Sequencing (WGBS) of a newborn and of a centenarian. The centenarian DNA exhibited a significant loss in DNA methylation and a poor correlation in the methylation status of neighboring CpGs throughout the genome. From a gene-regulatory region standpoint, we observed that the DNA hypomethylation events occurred mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. Most importantly, we extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray. The 450K DNA methylation approach enabled validation of the WGBS data and revealed additional age-related DNA methylation events. Interestingly, we also observed the DNA methylation fingerprint characteristic of a healthy aged cell in samples from patients with premature-aging disorders such as Hutchinson-Gilford progeria and Werner syndrome. Overall, we suggest that defects in the physiological DNA methylation profile contribute to the process of human aging. As the disease associated cells were immortalized B cells, the effect of EBV immortalization was determined in advance to the study using immortalized and naive B cells. DNA was quantified by Quant-iT PicoGreen dsDNA Reagent (Invitrogen) and the integrity was analyzed in a 1.3% agarose gel. Bisulfite conversion of 600 ng of each sample was perform according to the manufacturer's recommendation for Illumina Infinium Assay. Effective bisulphite conversion was checked for three controls that were converted simultaneously with the samples. 4 ul of bisulfite converted DNA were used to hybridize on Infinium HumanMethylation 450 BeadChip, following Illumina Infinium HD Methylation protocol. Chip analysis was performed using Illumina HiScan SQ fluorescent scanner. The intensities of the images are extracted using GenomeStudio (2010.3) Methylation module (1.8.5) software. Methylation score of each CpG is represented as beta value.
2012-06-12 | E-GEOD-33233 | biostudies-arrayexpress
Project description:We used microarray approach to establish demethylated specific genes profiles in early gastric cancer. We analyzed 11 gastric cancer cell lines and 32 pairs of gastric cancer and normal samples to discover methylation signatures specific to gastric cancer cells.
2011-05-31 | E-GEOD-25869 | biostudies-arrayexpress
Project description:Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. Integrating gene expression and methylation array analysis we identified novel candidate TSGs frequently methylated in melanoma. We validated the methylation status of the most promising TSGs using the highly sensitive, specific and comprehensive Sequenom Epityper assay in a large panel of melanoma cell lines and resected melanomas, and compared the findings with that from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. The effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis. Analysed samples consisted of 11 melanoma cell lines and 1 neonatal foreskin melanocyte pool as a reference. Melanoma cell lines overlap with members of the DNA copy number analysis series GSE9003 and expression profiling series GSE7127 . The matching copy number data GEO samples IDs are noted in characteristics: Matching CN Sample ID and characteristics: Matching expn Sample ID columns respectively.
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Project description:DNA methylation profiling of cancer and control samples. The Illumina GoldenGate Methylation Cancer Panel I was used to obtain DNA methylation profiles across 1,505 CpG sites CpGs distributed across 807 genes in blood DNA specimens. DNA samples were extracted from blood specimens, bisulfite treated and subsequently used for GoldenGate Methylation Cancer Panel I Array (Illumina) according to manufacturer’s protocol together with normalization methylated, hemimethylated and unmethylated DNA controls (Qiagen).
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