Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays

Wang, Li; Fidler, Carrie; Nadig, Nandita R.; Giagounidis, Aristoteles; Porta, Matteo Giovanni Della; Malcovati, Luca; Killick, Sally; Gattermann, Norbert; Aul, Carlo; Boultwood, Jacqueline; Wainscoat, James S.

doi:10.3324/haematol.12603

Cited by 39 publications

(31 citation statements)

References 27 publications

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“…2 This is reflected in its relatively good prognosis. 8,11 Previous studies have shown mutations in a limited number of genes, including TP53, JAK2 and ASXL1 9,10,34,46 in this subtype of MDS.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…2 The results of the analysis are listed in Online Supplementary Table S5. The del(5q) was characterized in all 33 cases.…”

Section: Copy Number Changes and Uniparental Disomy Analysismentioning

confidence: 99%

“…Recent molecular investigations have revealed additional genetic abnormalities in MDS, including microdeletions and loss of heterozygosity due to acquired uniparental disomy (UPD). 2 Interstitial deletion within the long arm of chromosome 5 [del(5q)] is one of the most frequent cytogenetic abnormalities observed in myeloid malignancies, occurring in approximately 10-20% of patients with de novo MDS 3 and in a similar proportion of patients with de novo AML. 4 In de novo MDS the del(5q) occurs either in isolation or together with other karyotypic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…Whole genome array data were available for all of them. 2 The genes with co-occurring mutations were ASXL1, WT1, SF3B1, TET2, DNMT3A, JAK2 and CBL (Figures 1 and 2).…”

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confidence: 99%

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Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

et al. 2013

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Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphismarray technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q-syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies <20%, likely below the detection limit of traditional sequencing methods. Genomic array data showed that cases of advanced del(5q) myelodysplastic syndrome had a complex background of cytogenetic aberrations, often encompassing genes involved in myeloid disorders. Our study is the first to investigate the molecular pathogenesis of early and advanced del(5q) myelodysplastic syndromes using next-generation sequencing technology on a large panel of genes frequently mutated in myeloid malignancies, further illuminating the molecular landscape of del(5q) myelodysplastic syndromes.

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…2 The results of the analysis are listed in Online Supplementary Table S5. The del(5q) was characterized in all 33 cases.…”

Section: Copy Number Changes and Uniparental Disomy Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Whole genome array data were available for all of them. 2 The genes with co-occurring mutations were ASXL1, WT1, SF3B1, TET2, DNMT3A, JAK2 and CBL (Figures 1 and 2).…”

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confidence: 99%

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Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

et al. 2013

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“…A common deleted region (CDR) has been identified covering the area of 5q31-32, where two alternative missing segments have been reported, one proximal deleted entity associated with advanced MDS conditions and a second distal deleted region associated with the 5q-deletion syndrome with better prognosis (9). Loss of the CDR region ablates 44 genes and results in haploinsufficiency conditions for many of these gene products, where the levels of gene products are not sufficient for the physiological cell function.…”

Section: Introductionmentioning

confidence: 99%

SPARC ectopic overexpression inhibits growth and promotes programmed cell death in acute myeloid leukemia transformed from myelodysplastic syndrome cells, alone and in combination with Ara-C treatment

et al. 2015

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Abstract. Secreted protein acidic and rich in cysteine (SPARC) has a complex and pleiotropic biological role in cell life during disease. The role of SPARC in myelodysplastic syndrome (MDS) is not yet fully understood. In the present study, we investigated the role of SPARC protein overproduction in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line transformed from MDS. SKM-1 cells were infected with the pGC-GV-SPARC vector. The cells were then assessed for proliferation and cell death following treatment with low-dose cytosine arabinoside (Ara-C). The microarray analysis results revealed that samples from SPARC-overexpressed cells compared to SPARC protein, in SKM-1 cells led to proliferation inhibition and promoted programmed cell death and these effects were greater when treated with Ara-C. The mRNA and protein expression levels of SPARC were detected by SPARC overexpression in cells treated with Ara-C resulting in a significant upregulation of the mixed lineage kinase domain-like (MLKL) gene expression and five other genes. The results showed that the necrotic signaling pathway may play a role when the two conditions were combined via the upregulation of the MLKL protein. MLKL upregulation in SPARC overexpressed cells treated with Ara-C, indicates necrosis as a possible cell death process for the SKM-1 cells under these stringent conditions.

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The myelodysplastic syndromes

Mecucci¹,

Battista²,

Nofrini³

2016

The Genetic Basis of Haematological Cancers

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Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays

Cited by 39 publications

References 27 publications

Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

SPARC ectopic overexpression inhibits growth and promotes programmed cell death in acute myeloid leukemia transformed from myelodysplastic syndrome cells, alone and in combination with Ara-C treatment

The myelodysplastic syndromes

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