Acquired Copy Number Alterations in Adult Acute Myeloid Leukemia Genomes
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ABSTRACT:
PROVIDER: PRJNA75573 | ENA |
REPOSITORIES: ENA
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Project description:Identification of Acquired Copy Number Alterations and Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia Using High-Resolution Single Nucleotide Polymorphism Analysis Recent advances in genome-wide single nucleotide polymorphism (SNP) analyses have revealed previously unrecognized microdeletions and uniparental disomy (UPD) in a broad spectrum of human cancers. As acute myeloid leukemia (AML) represents a genetically heterogeneous disease, this technology might prove helpful especially for cytogenetically normal AML (CN-AML) cases. Thus, we performed high-resolution SNP analyses in 157 adult cases of CN-AML. Regions of acquired UPD were identified in 12% of cases and most frequently affected chromosomes 6p, 11p, and 13q. Notably, acquired UPD was invariably associated with mutations in NPM1 or CEBPA that impair hematopoietic differentiation (P=0.008), suggesting that UPDs may preferentially target genes that are essential for proliferation and survival of hematopoietic progenitors. Acquired copy number alterations (CNAs) were detected in 49% of cases with losses found in two or more cases affecting e.g. chromosome bands 3p13-p14.1 and 12p13. Furthermore, we identified two cases with a cryptic t(6;11) as well as several non-recurrent aberrations pointing to leukemia relevant regions. With regard to clinical outcome, there appeared to be an association between UPD 11p and UPD 13q cases with overall survival. These data demonstrate the potential of high-resolution SNP analysis for identifying genomic regions of potential pathogenic and clinical relevance in AML.
2009-12-01 | GSE19101 | GEO
Project description:<p>We performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using the Affymetrix Genome-Wide Human SNP array 6.0 containing 1.85 million features. Acquired copy number alterations (CNA) were confirmed using an independent, higher resolution, custom array comparative genomic hybridization platform.</p> <p>A total of 201 somatic CNA were found in the 86 AML genomes (mean 2.34 CNA/genome), with FAB M6 and M7 AML genomes containing the most changes (10-29 CNA/genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, while 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several regions contained CNA in multiple AML genomes. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. Array data are available online at <a href="http://www.ncbi.nlm.nih.gov/geo/" target="_blank">http://www.ncbi.nlm.nih.gov/geo/</a> as GEO accession #GSE10358. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes and 6/8 UPD regions occurred in samples with a normal karyotype. Collectively, 40% of AML genomes contained alterations not found with cytogenetics, and 96% of these regions contained known or novel AML associated genes. 43/86 AML genomes had no CNA or UPD at this level of resolution. The number of CNA per genome was not associated with overall survival, independent of cytogenetic classification.</p> <p>In this study of 86 adult AML genomes, subcytogenetic CNAs or UPD did not add prognostic information to standard cytogenetics. However, arrays identified many somatically mutated oncogenes and tumor suppressor genes, and also genes not previously implicated in AML that may be relevant for pathogenesis.</p> <p>AML CNA segments from 86 adult AML patients are available through dbVar at <a href="ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009">ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009</a>.</p>
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Project description:Eukaryotic cells maintain multiple copies of the mitochondrial genome, which is essential for cellular metabolism. Accordingly, alterations in the mitochondrial DNA (mtDNA) copy number are associated with severe human diseases and ageing. However, the mechanisms through which cells regulate mtDNA copy number and the cellular consequences of altered copy number remain poorly understood. Here, using budding yeast as a model, we show that mtDNA copy number is determined by the amount of three limiting factors, Mip1, Abf2, and Rim1. By synthetically tuning the concentrations of only these three proteins, we can modulate mtDNA dosage inside the cell. This revealed that cells are surprisingly robust to mtDNA copy number alterations, with increased copy numbers even accelerating cell growth. Our findings suggest that this robustness is due to protein dosage compensation and independent regulation of mitochondrial morphology. Mechanistically, we identified a critical role of the retrograde signalling pathway for this adaptation. We show that signalling from mitochondria to the nucleus is upregulated in cells with higher mtDNA copy number, and disruption of this regulation diminishes their faster growth. Taken together, our work reveals regulatory principles that allow cells to adapt to mtDNA copy number alterations.
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Project description:<p>We performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo
AML using the Affymetrix Genome-Wide Human SNP array 6.0 containing 1.85 million features. Acquired copy number alterations (CNA)
were confirmed using an independent, higher resolution, custom array comparative genomic hybridization platform.</p>
<p>A total of 201 somatic CNA were found in the 86 AML genomes (mean 2.34 CNA/genome), with FAB M6 and M7 AML genomes containing the
most changes (10-29 CNA/genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, while 40% of patients with
an abnormal karyotype had additional CNA detected by SNP array, and several regions contained CNA in multiple AML genomes.
The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size.
Array data are available online at <a href="http://www.ncbi.nlm.nih.gov/geo/" target="_blank">http://www.ncbi.nlm.nih.gov/geo/</a>
as GEO accession #GSE10358. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes and 6/8 UPD regions
occurred in samples with a normal karyotype. Collectively, 40% of AML genomes contained alterations not found with cytogenetics,
and 96% of these regions contained known or novel AML associated genes. 43/86 AML genomes had no CNA or UPD at this level of resolution.
The number of CNA per genome was not associated with overall survival, independent of cytogenetic classification.</p>
<p>In this study of 86 adult AML genomes, subcytogenetic CNAs or UPD did not add prognostic information to standard cytogenetics.
However, arrays identified many somatically mutated oncogenes and tumor suppressor genes, and also genes not previously implicated
in AML that may be relevant for pathogenesis.</p>
<p>AML CNA segments from 86 adult AML patients are available through dbVar at
<a href="ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009">ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009</a>.</p>
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Project description:In order to benchmark the reproducibility of Affymetrix Genome-Wide Human SNP Array 6.0 for detecting copy-number alterations, we performed replicate hybridizations of 3 tumor cell lines and 2 paired normal cell lines obtained from the American Type Culture Collection (ATCC). We calculated copy numbers at each SNP probeset by a custom copy-number pipeline (PMID: 18772890). For each cell line, copy number data from replicate arrays are supplied in the accompanying matrix files. For each SNP probeset, we calculated the median copy number across replicate arrays. We compared the copy-number alterations detected by Circular Binary Segmentation segmentation of these arrays with statistical analyses of short sequence reads obtained from the Illumina/Solexa 1G GenomeAnalyzer. Shotgun sequencing results can be found in the NCBI Short Read Archive, accession number SRP000246 Keywords: disease state analysis
2008-11-14 | GSE13372 | GEO