Genome-wide signatures of differential DNA methylation and gene expression in pediatric ALL
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jessica Nordlund
PROVIDER: E-GEOD-49032 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. The DNA methylation levels of primary pediatric ALL samples taken at diagnosis (n= 764), remission(n=86), first relapse (n=27), second relapse (n=5), fractionated blood cells from healthy blood donors (n=51), and methylation +/- controls (n=11) were analyzed with the Illumina Infinium HumanMethylation 450k BeadChips. One ALL sample was run in duplicate (technical replicate).
2013-09-18 | E-GEOD-49031 | biostudies-arrayexpress
Project description:We surveyed the genome-wide DNA methylation levels and gene expression patterns in patients with pediatric acute lymphoblastic leukemia. Using Affymetrix U133 Plus 2.0 GeneChips, we identified a relatively small set of CpG sites that are highly correlated with gene expression. Genome-wide expression analysis of 108 primary ALL samples by Affymetrix Human Genome U133 Plus 2.0 GeneChips used to investigate relationships between subtype-specific DNA methylation patterns and gene expression in 93 patients with both gene expression and DNA methylation data.
2013-09-18 | E-GEOD-47051 | biostudies-arrayexpress
Project description:B-cell precursor acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer. Although the genetic origin of the disease remains unclear, epigenetic modifications including DNA methylation are suggested to contribute significantly to leukemogenesis. We assessed the DNA methylation status of 402,842 CpG-sites across the genome (Illumina 450k array) in tumor and remission samples of 46 pre-B ALL patients, thus generating the most comprehensive single CpG-site resolution pre-B ALL methylomes so far. Unsupervised hierarchical clustering of CpG-site neighborhood, protein-coding gene, or miRNA gene associated methylation levels separated the tumor cohort according to major pre-B ALL subtypes, and methylation in CpG islands, shores, and in regions around the transcription start site of protein-coding genes strongly correlated with transcript expression. Focusing on samples carrying the t(12;21)(p13;q22) translocation (ETV6-RUNX1 fusion gene) we identified subtype-specific methylation of 430 CpG-sites. Pathway analyses implied the associated genes in hematopoiesis and cancer. Further intersection with transcriptome data identified methylation to impact expression of 18 genes. In summary, our data illustrate the power of methylation profiling to classify leukemic subtypes and to identify subtype-specific methylation markers. Further, we demonstrate that integration of methylome and transcriptome alterations allows the study of downstream effects of individual genomic rearrangements in cancer. Bisulfite converted DNA of tumor (isolated on day of diagnosis) and remission (isolated after disease remission) samples derived from 46 patients of French-Canadian origin diagnosed with pre-B ALL were analyzed on the Illumina Infinium HumanMethylation 450k BeadChips.
2013-06-04 | E-GEOD-38235 | biostudies-arrayexpress
Project description:Methylation profiling can reveal patterns of hypermethlation and hypomethylation associated with distinct biologic subtypes of acute lymphoblastic leukemia (ALL). We performed methylation profiling of Down syndrome ALL cases and controls to identify unique biologic features of this ALL subgroup. Ficoll-enriched, cryopreserved bone marrow aspirate samples were obtained from patients with B-precursor ALL at diagnosis and in remission
2011-12-01 | E-GEOD-20872 | biostudies-arrayexpress
Project description:Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1. Genomic DNA (500ng) was bisulfite converted using EZ DNA methylation Kit (Zimo Research) following the manufacturer’s protocol with modification for Illumina Infinium Methyaltion arrays. Samples were hybridized to Infinium Human Methylation 450K BeadChips (Illumina) according to the manufacturer’s protocol. Arrays were scanned on Iscan (Illumina). Data was background corrected, normalized to internal controls and QC was performed at the probe and sample level. COMBAT was used to remove batch effects (Johnson et al., 2007). Contributor: The Australian Ovarian Cancer Study Group
2015-05-19 | E-GEOD-65820 | biostudies-arrayexpress
Project description:Background: Epigenetic marks, like asthma, are heritable. They are influenced by the environment, direct the maturation of T cellslymphocytes, and have been shown to enhance the development of allergic airways disease in mice. Thus, we hypothesized that epigenetic marks are associated with allergic asthma in inner-city children. Methods: We compared methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs) from inner city children aged 6-12 years with persistent atopic asthma children and healthy controls. Results were externally validated with the GABRIELA study population. Results: Comparing asthmatics (N=97) to controls (N=97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthmatics, including IL-13, RUNX3, and a number of specific genes relevant to natural killer cells (KIR2DL4, KIR2DL3, KIR3DL1, and KLRD1) and T cells lymphocytes (TIGIT). 14 differentially methylated regions (DMRs) were associated with the serum IgE concentration of IgE, including RUNX3. These results were internally and externally validated with a global methylation assessment using a different methodology in our inner-city cohort and an independent European cohort (GABRIELA). Hypo- and hypermethylated genes tended to be associated with increased and decreased gene expression, respectively (P<0.6x10-11 for asthma and ; P<0.01 for IgE). To further explore the relationship between methylation and gene expression, we created a matrix of genomic changes in methylation versus transcriptional changes (methyl eQTL) for asthma, and identified cis- and trans-regulated genes whose expression was related to asthma asthma-associated methylation marks. peripheral blood mononuclear cells (PBMCs) from 97 atopic asthmatic and 97 nonatopic nonasthmatic children
2015-02-02 | E-GEOD-40576 | biostudies-arrayexpress
Project description:Background & Aims: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting non-invasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. Methods: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0?1 (mild) and F3?4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. Results: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P<.05). Methylation at FGFR2, MAT1A, and CASP1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, whereas genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and under-expressed. Conclusions: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD. Three technical replicates were included for quality control along with 35 mild NAFLD (33 unique samples) and 24 advanced NAFLD (23 unique sample). One sample per technical duplication was randomly included for a total of 56 NAFLD samples used for study.
2013-08-30 | E-GEOD-49542 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-02-02 | E-GEOD-40736 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-08-30 | E-GEOD-31803 | biostudies-arrayexpress
Project description:Our data show Satb1 deficiency leads to alterations in DNA cytosine methylation and a commitment-primed epigenetic state in HSCs. Examination of DNA cytosine methylation in wild type HSC and differentiation-committed progenitors as well as in wild type HSC and HSC lacking Satb1 (n=2 each).
2013-04-07 | E-GEOD-44304 | biostudies-arrayexpress