Unknown,Transcriptomics,Genomics,Proteomics

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Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

ABSTRACT: Mutations in the TET2 gene are frequent in myeloid disease, although their biological and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using ‘Next-Generation’ sequencing (NGS) for TET2 aberrations; 91 of whom were also subjected to SNP6 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) ≥10%, were identified in 39 of 320 (12%) MDS and 16 of 35 (46%) CMML patients (p<0.001). Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. ‘Deeper’ sequencing of 96 patient samples identified 4 additional mutations (RMA 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells in addition to CD34+ and total bone-marrow cells (23.5%, 38.5% and 43% RMA respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression or the JAK2V617F 46/1 haplotype between TET2-mutated and non-mutated patients. There was no significant prognostic association between TET2 mutations and WHO subtypes, IPSS score, cytogenetic status, or transformation to AML. On multivariate analysis, age (>50yrs) was associated with a higher incidence of TET2 mutation (p=0.02). Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from bone marrow or peripheral blood samples. Copy number and acquired UPD analysis of Affymetrix SNP 6.0 arrays was performed for 91 cases with Myelodysplastic syndromes.

ORGANISM(S): Homo sapiens

SUBMITTER: Bartlomiej Przychodzen

PROVIDER: E-GEOD-23300 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases. We performed a supervised class comparison analysis comparing 31 TET-mutated AML cases (TET2 mut) vs. 302 TET2-wildtype AML cases (TET wt) to see if a specific gene expression pattern associated with the presence of the identified TET2 mutations could be determined. No technical replicates were performed.

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Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

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