Immune-related gene expression signatures associated with progression of myelodysplastic neoplasms
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE348527 | GEO | 2026/09/30
REPOSITORIES: GEO
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Project description:In this study, to obtain a complete registry of genetic lesions in MDS and to identify novel therapeutic targets, we performed SNP array analysis and whole exome analysis for novel mutations using high-throughput sequencing technologies. In whole exome analysis, paired CD3-positive T cells were used as a normal control. By comparing sequences in tumors and paired T cells, 268 non-synonymous somatic mutations were confirmed with an overall true positive rate of 53.9 %, including 206 missense, 25 nonsense, and 10 splice site mutations, and 27 frameshift-causing insertions/deletions (indels). The mutations of the known gene targets, however, accounted for only 12.3 % of all detected mutations (N = 33), and the remaining 235 mutations involved previously unreported genes. Combined with the genomic copy number profile obtained by SNP array karyotyping, this array of somatic mutations provided a landscape of myelodysplasia genomes. Copy number analysis of Affymetrix 250K SNP arrays was performed for 29 MDS or related neoplasms and paired 29 germline samples.
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Project description:Prior studies using DNA microarray platforms have shown alterations of gene expression profiles (GEPs) of marrow cells in myelodysplastic syndromes (MDS). Using the increased sensitivity and accuracy of high-throughput RNA sequencing (RNA-Seq) for detecting and quantifying mRNA transcripts, our study has demonstrated novel significant differences in GEPs between MDS and normal CD34+ marrow cells with 41 genes identified as disease classifiers. Additionally, two main clusters of GEPs distinguished patients based on their major clinical features, particularly between those whose disease remained stable (sMDS) vs patients whose illness transformed to acute myeloid leukemia within 12 months (tMDS). The genes whose expression was associated with disease outcome were involved in functional pathways and biologic processes highly relevant for MDS. Exomic analysis identified MDS-associated pathogenic mutations in virtually all patients tested. MDS subgroups with spliceosome mutations demonstrated distinct differential isoform usage and expression and consequent dysregulation of distinct biological functions. This combination of clinical, transcriptomic and exomic findings provides valuable molecular insights into the mechanisms underlying MDS and its progression to a more aggressive stage and also facilitates prognostic characterization of MDS patients.
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Project description:The progressive mechanism of myelodysplastic syndrome (MDS) remains unknown. We report that ROBO1 and ROBO2 are identified as novel progression-related somatic mutations using whole-exome and targeted sequencing in six of 16 (37.5%) paired MDS patients undergoing disease progression. To investigated the effect of ROBO1 or ROBO2 on ROBO1/2 CN number and LOH, we employed a Cytosan 750K chip to analyze the copy-number variations (CNVs) and loss of heterogeneity (LOH) in MDS patients with ROBO1&2 mutations. Copy number and LOH analysis of Affymetrix CytoScan 750K array was performed for 14 MDS patients with ROBO1 or ROBO2 mutations
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Project description:We report the identification of five subtypes of myelodysplastic syndromes (MDS) identified via unsupervised classification of DNA methylation (DNAm) profiles. Bisulfite padlock probe sequencing (BSPP) was used to measure DNAm of ~500,000 unique CpGs covering 140,749 non-overlapping regulatory regions across the genome in bone marrow DNA samples from 141 patients with MDS. Application of a non-negative matrix factorization (NMF) decomposition of DNAm profiles identified five consensus clusters described by five NMF components as the most stable grouping solution.
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Project description:Control of oxidative stress in the bone marrow (BM) is key for maintaining the balance between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an oxidative stress marker in BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox.
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Project description:In a two-stage study we investigated levels of Immunoglobulin G (IgG) reactivity in plasma from Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) post MDS patients (59 and 16 cases respectively) as compared to healthy cohort (34). In Stage I we utilized high-throughput protein arrays (23 232 total signals, in duplicate) to identify proteins of high-interest. In Stage II we designed new protein arrays (352 total signals, in duplicate) to further focus on 25 of the proteins from Stage I and expanded to a larger cohort, including both male and female samples (161 MDS and 43 AML patients; 112 healthy controls). Stage I resulted in 35 proteins displaying increased IgG reactivity in patients as compared to the healthy controls (P< 4.3 x10-07, Bonferroni Corrected P<0.01). This protein subset included 14 proteins associated with cancer, 12 with apoptosis, and 3 with the NFAT Regulation canonical pathway. Using the focused arrays we performed a classification of MDS patients and healthy controls. Stage II subsequently identified a high-interest focused set of 3 proteins, namely AKT3, FCGR3A and ARL8B displaying aberrant increased reactivity in patient subgroups, in concordance with Stage I. Autoantibody reactivity against specific proteins provides complementary information to other known molecular signatures for MDS and may enhance our capabilities for detecting and classifying MDS. In the study presented here, MDS patients were classified into Stable, Transforming or AML post MDS (L) classes retrospectively. The different patients were compared to a healthy cohort to assess increased autoantibody reactivity to specific patients as opposed to healthy groups Stage 1 of Study: 111 Files Analyzed, 37 sMDS, 22 tMDS, 16 AML(L), 34 Healthy and 2 Negative Controls (used to eliminate non-plasma signals)
2013-11-21 | E-GEOD-48153 | biostudies-arrayexpress
Project description:In a two-stage study we investigated levels of Immunoglobulin G (IgG) reactivity in plasma from Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) post MDS patients (59 and 16 cases respectively) as compared to healthy cohort (34). In Stage I we utilized high-throughput protein arrays (23 232 total signals, in duplicate) to identify proteins of high-interest. In Stage II we designed new protein arrays (352 total signals, in duplicate) to further focus on 25 of the proteins from Stage I and expanded to a larger cohort, including both male and female samples (161 MDS and 43 AML patients; 112 healthy controls). Stage I resulted in 35 proteins displaying increased IgG reactivity in patients as compared to the healthy controls (P< 4.3 x10-07, Bonferroni Corrected P<0.01). This protein subset included 14 proteins associated with cancer, 12 with apoptosis, and 3 with the NFAT Regulation canonical pathway. Using the focused arrays we performed a classification of MDS patients and healthy controls. Stage II subsequently identified a high-interest focused set of 3 proteins, namely AKT3, FCGR3A and ARL8B displaying aberrant increased reactivity in patient subgroups, in concordance with Stage I. Autoantibody reactivity against specific proteins provides complementary information to other known molecular signatures for MDS and may enhance our capabilities for detecting and classifying MDS. In the study presented here, MDS patients were classified into Stable, Transforming or AML post MDS (L) classes retrospectively. The different patients were compared to a healthy cohort to assess increased autoantibody reactivity to specific patients as opposed to healthy groups Stage 2 of study: 633 Files analyzed for: 316 Patients in duplicate and a negative control. The proteins on the array were selected following a first stage using ProtoArrays
2013-11-21 | E-GEOD-48154 | biostudies-arrayexpress
Project description:In a two-stage study we investigated levels of Immunoglobulin G (IgG) reactivity in plasma from Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) post MDS patients (59 and 16 cases respectively) as compared to healthy cohort (34). In Stage I we utilized high-throughput protein arrays (23 232 total signals, in duplicate) to identify proteins of high-interest. In Stage II we designed new protein arrays (352 total signals, in duplicate) to further focus on 25 of the proteins from Stage I and expanded to a larger cohort, including both male and female samples (161 MDS and 43 AML patients; 112 healthy controls). Stage I resulted in 35 proteins displaying increased IgG reactivity in patients as compared to the healthy controls (P< 4.3 x10-07, Bonferroni Corrected P<0.01). This protein subset included 14 proteins associated with cancer, 12 with apoptosis, and 3 with the NFAT Regulation canonical pathway. Using the focused arrays we performed a classification of MDS patients and healthy controls. Stage II subsequently identified a high-interest focused set of 3 proteins, namely AKT3, FCGR3A and ARL8B displaying aberrant increased reactivity in patient subgroups, in concordance with Stage I. Autoantibody reactivity against specific proteins provides complementary information to other known molecular signatures for MDS and may enhance our capabilities for detecting and classifying MDS. In the study presented here, MDS patients were classified into Stable, Transforming or AML post MDS (L) classes retrospectively. The different patients were compared to a healthy cohort to assess increased autoantibody reactivity to specific patients as opposed to healthy groups
2013-11-21 | GSE48154 | GEO
Project description:In a two-stage study we investigated levels of Immunoglobulin G (IgG) reactivity in plasma from Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) post MDS patients (59 and 16 cases respectively) as compared to healthy cohort (34). In Stage I we utilized high-throughput protein arrays (23 232 total signals, in duplicate) to identify proteins of high-interest. In Stage II we designed new protein arrays (352 total signals, in duplicate) to further focus on 25 of the proteins from Stage I and expanded to a larger cohort, including both male and female samples (161 MDS and 43 AML patients; 112 healthy controls). Stage I resulted in 35 proteins displaying increased IgG reactivity in patients as compared to the healthy controls (P< 4.3 x10-07, Bonferroni Corrected P<0.01). This protein subset included 14 proteins associated with cancer, 12 with apoptosis, and 3 with the NFAT Regulation canonical pathway. Using the focused arrays we performed a classification of MDS patients and healthy controls. Stage II subsequently identified a high-interest focused set of 3 proteins, namely AKT3, FCGR3A and ARL8B displaying aberrant increased reactivity in patient subgroups, in concordance with Stage I. Autoantibody reactivity against specific proteins provides complementary information to other known molecular signatures for MDS and may enhance our capabilities for detecting and classifying MDS. In the study presented here, MDS patients were classified into Stable, Transforming or AML post MDS (L) classes retrospectively. The different patients were compared to a healthy cohort to assess increased autoantibody reactivity to specific patients as opposed to healthy groups
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