Bioinformatic evaluation and comparison of parallel aSNP and aCGH analyses of myelodysplastic syndromes patients with normal karyotype
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50897 | GEO | 2017/01/01
SECONDARY ACCESSION(S): PRJNA219313
REPOSITORIES: GEO
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Project description:About 40% of patients with myelodysplastic syndromes (MDS) present with a normal karyotype and they are facing different courses of disease. To advance the biological understanding and find molecular prognostic markers we performed a high resolution oligonucleotide array study of 107 MDS patients (FAB) with a normal karyotype. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 had an additional 5q31.2 deletion of the AML/MDS region; the smallest deletion identified so far and includes the putative tumor suppressor (ts) genes EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total 42/107 (39%) cases had genomic imbalances, deletions were more frequent than gains. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS but points to interesting genes which may have diagnostic and prognostic impact. Array CGH experiment, MDS tumor cells vs. control DNA. Total of 107 tumors.
2011-01-30 | E-GEOD-24602 | biostudies-arrayexpress
Project description:About 40% of patients with myelodysplastic syndromes (MDS) present with a normal karyotype and they are facing different courses of disease. To advance the biological understanding and find molecular prognostic markers we performed a high resolution oligonucleotide array study of 107 MDS patients (FAB) with a normal karyotype. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 had an additional 5q31.2 deletion of the AML/MDS region; the smallest deletion identified so far and includes the putative tumor suppressor (ts) genes EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total 42/107 (39%) cases had genomic imbalances, deletions were more frequent than gains. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS but points to interesting genes which may have diagnostic and prognostic impact.
2011-01-30 | GSE24602 | GEO
Project description:This study describes a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is the first description of a recurrent telomere fusion event in myeloid malignancy. The derivative chromosome is further characterised by the presence of nucleolus organiser region material from the chromosome 22 short arm, loss of the putative tumour suppressor gene at 20q12 and secondary rearrangements including gain or amplification of 20q material adjacent to the deletion encompassing 20q12. The presence of residual telomere sequence at the site of translocation in three of the four cases is compelling support for telomere fusion, and supports previous evidence that over half of dicentric chromosomes involving 20q are produced by telomere fusion events. We propose that the sequence of events producing this chromosome abnormality is initial formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, followed by breakage-fusion-bridge cycles causing 20q12 deletion and 20q11.2 gain which provide a growth advantage to the cell. Selection of these clones contributes to leukaemogenesis. Finding recurrent patterns in the complex genome reorganisation events which characterise poor prognosis, complex karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies. The sample consists of leukaemia specimens from three different cases of AML and MDS. The consistent feature was the presence of a dicentric chromosome formed from chromosomes 20 and 22.
2016-06-30 | E-GEOD-64050 | biostudies-arrayexpress
Project description:Isolated deletions of the long arm of chromosome 5 (del(5q)) are observed in 10% of myelodysplastic syndromes (MDS) and are associated with a more favorable prognosis, although the clinical course varies considerably. If one or more additional chromosomal aberration/s are present this correlates with a significant shorter overall survival. To assess the frequency of hidden abnormalities in cases with an isolated cytogenetic del(5q), we have performed a genome wide high resolution 44K 60mer oligonucleotide array CGH study using DNA from bone marrow cells of 12 MDS and one AML patient. Additional chromosomal aberrations were identified in three of 13 cases (23%): in one case, a single additional hidden 5.6 Mb deletion of 13q14 and in two cases, multiple larger aberrations involving many chromosomes. Fluorescence in situ hybridization (FISH) demonstrated that aberrations present in only 10% of the bone marrow cells were detectable by aCGH. Furthermore with oligonucleotide aCGH the deletion end points in 5q were mapped precisely, revealing a cluster of proximal break points in band q14.3 (n=8) and a distal cluster between bands q33.2 to q34 (n=11). This study shows the high resolution of oligonucleotide CGH arrays for precisely mapping genomic alterations and for refinement of deletion end points. In addition the high sensitivity of this method enables the study of whole bone marrow cells from MDS patients, a disease with a low blast count. Future studies of more patients with isolated del(5q) for hidden abnormalities will be necessary to evaluate the impact of these on the variable prognosis in these patients and to further define new genetic subgroups. Keywords: Myelodysplastic syndromes, MDS, array CGH, del(5q), hidden aberrations
2007-09-11 | GSE8804 | GEO
Project description:The array comparative genomic hybridization (aCGH) was perform to identify regions with genomic imbalance in lung cancer.The aCGH analysis detected a total of 325 regions with genomic imbalance in all 8 lung cancer samples, ranging from focal rearrangements (70 kb–5 Mb) to chromosome-arm alterations with chromosomal segments amplification or deletion. Among these mutations, a total of 115 genomic imbalances were discovered occurring at high frequency varying from 25% to 50%.
2016-11-17 | GSE89927 | GEO
Project description:Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by ineffective hematopoiesis and high propensity to leukemias. Although a number of gene targets have been identified, in many MDS cases, particular genetic targets are unknown. In this study, we performed genome-wide profiling of copy number (CN) abnormalities and allelic imbalances in MDS genomes in order to clarify the distribution of LOH (loss of heterozygosity) and identify their target genes. We analyzed a total of 171MDS and MDS/MPD specimens, including 7 RA/RARS, 23 RCMD/RCMD-RS, 6 5q-syndrome, 30 RAEB-1, 40 RAEB-2, 4 therapy related-MDS/AML, 5 MDSu, 17 CMML-1, 16 CMML-2, 24 overt AML, using high-density SNP arrays. The data were analyzed by CNAG/AsCNAR software we specifically developed for allele-specific CN analysis and sensitive LOH detection. MDS showed characteristic CN profiles in SNP array analysis. Of particular interest is the finding of high frequency of CN-neutral LOH (Uniparental disomy,UPD), which were observed in 51 of 171 (30%) MDS cases. They preferentially involved 1p, 1q, 4q, 7q, 11q, 17p and other chromosomal segments, which were associated with homozygous mutations of both loss-of-function mutations and gain-of function mutations of tumor suppressor genes and cellular oncogenes, including TP53 (17p UPD), AML1/RUNX1 (21q UPD), Nras and cMPL (1p UPD), JAK-2 (9p UPD), and FLT3 (13q UPD). Next we tried to identify a new gene target in 11q UPD, which was most common UPD region in this study and many of these cases were CMML with a normal karyotype. The minimum 11q UPD segment is about 2Mb which existed in 11q23. We sequenced coding exons of c-cbl and detected homozygous mutations in 8 of 9 MDS cases with 11q UPD (CMML= 5, RAEB= 3, overt leukemia= 1), but very rare in cases without 11q UPD (1/162), demonstrating that the mutation is tightly linked to 11q UPD. These mutations were 8 point mutations and 1 micro-deletion, they were accumulated in the linker or RING domain. These c-cbl mutants can transform NIH3T3 in a dominant manner and these mutants are phosphorylated and activate PI3K-Akt pathway. To investigate the functions of these mutants in hematopoietic cells, we introduced these mutants into c-kit(+)Sca1(+)Lin(-) murine bone marrow cells, it prolonged replating capacity of these hematopoietic progenitors. Keywords: SNP-chip To identify oncogenic lesions in MDS, we performed a genome-wide analysis of primary MDS samples using high-density SNP arrays (Affymetrix GeneChip).
2010-04-09 | E-GEOD-15187 | biostudies-arrayexpress
Project description:This study describes a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is the first description of a recurrent telomere fusion event in myeloid malignancy. The derivative chromosome is further characterised by the presence of nucleolus organiser region material from the chromosome 22 short arm, loss of the putative tumour suppressor gene at 20q12 and secondary rearrangements including gain or amplification of 20q material adjacent to the deletion encompassing 20q12. The presence of residual telomere sequence at the site of translocation in three of the four cases is compelling support for telomere fusion, and supports previous evidence that over half of dicentric chromosomes involving 20q are produced by telomere fusion events. We propose that the sequence of events producing this chromosome abnormality is initial formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, followed by breakage-fusion-bridge cycles causing 20q12 deletion and 20q11.2 gain which provide a growth advantage to the cell. Selection of these clones contributes to leukaemogenesis. Finding recurrent patterns in the complex genome reorganisation events which characterise poor prognosis, complex karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies.
2016-06-30 | GSE64050 | GEO
Project description:AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a later onset, a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p and 7q, as well as fast progression of the disease with extremely poor prognosis. We and other have shown that the MLL gene is over expressed in amplified cases, however, in most of the cases the amplified region is not restricted to the MLL locus. In the present study we investigated 19 patients with AML/MDS and MLL gain/amplification [15 AML (two secondary, following MDS and PV, and three therapy related) and 4 MDS cases (two therapy related)]. By means of array CGH performed in 12 patients (GSE9928) we were able to delineate the minimal deleted regions within 5q, 17p and 7q and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases were used to define the candidate genes within these regions. Interestingly, analysis of our data suggests an interdependency of genes influenced by losses of 5q and 17p and expression of genes present in 11q23-25. Additionally, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from all other types of AML, thus, indicating specific pathogenesis present in this entity. Experiment Overall Design: In this study, gene expression profiling performed for 15 AML patients. Experiment Overall Design: aCGH analysis performed on 12 DNA samples derived from patients with AML, preselected for the presence of MLL amplifications, were analysed on a submegabase resolution BAC array. No replicates, no dye swap was done (GSE9928).
2008-11-22 | E-GEOD-10258 | biostudies-arrayexpress
Project description:We used microarray CGH analysis with a tiling path BAC DNA microarray to profile DNA copy number alterations in 164 serous ovarian adenocarcinomas. Survival probabilities modelled by proportional hazards were used to stratify cases into good, intermediate or poor survival groups. Comparison of aCGH data from these groups was used to identify genomic alterations associated with patient survival. A total of 984 cases of serous ovarian adenocarcinoma from three different studies were combined and Cox proportional hazards used to model survival using patient age, tumour stage and residual disease status as covariates. Survival probabilities (Pr) were extracted for all cases and used to stratify 384 cases for which microarray CGH data was available. From these, we identified 70 cases with poor survival (Pr>0.784) and 70 cases with good survival (Pr<0.35). aCGH data from these cases was provided to an iterative Support Vector Machine (SVM) routine to detect copy number changes associated with survival. Candidate regions were then validated by survival analysis in all 384 cases for which aCGH data was available. This series contains aCGH data from 164 tumours from the MALOVA collection.
2012-05-31 | E-GEOD-29503 | biostudies-arrayexpress
Project description:Identification of DNA copy number imbalances in 22 spontaneous canine osteosarcoma cases using array comparative genomic hybridization (aCGH) analysis
2013-11-01 | E-MTAB-1986 | biostudies-arrayexpress