Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Novel and highly recurrent chromosomal alterations in SÃ©zary syndrome

ABSTRACT: This study was designed to identify highly recurrent genetic alterations typical of SÃ©zary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in SÃ©zary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008;68(8):2689â98] Keywords: aCGH, COBRA, FISH, PLA In this multicenter study, we aimed to obtain a detailed catalogue of numerical and structural chromosomal abnormalities in a group of 20 well-defined Sz patients using high-resolution array-based CGH in combination with combined binary ratio labeling (COBRA), fluorescence in situ hybridization (FISH), and in situ proximity ligation assays (PLA).

ORGANISM(S): Homo sapiens

SUBMITTER: Maarten Vermeer

PROVIDER: E-GEOD-16384 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Novel and highly recurrent chromosomal alterations in Sézary syndrome.

Vermeer Maarten H MH van Doorn Remco R Dijkman Remco R Mao Xin X Whittaker Sean S van Voorst Vader Pieter C PC Gerritsen Marie-Jeanne P MJ Geerts Marie-Louise ML Gellrich Sylke S Söderberg Ola O Leuchowius Karl-Johan KJ Landegren Ulf U Out-Luiting Jacoba J JJ Knijnenburg Jeroen J Ijszenga Marije M Szuhai Karoly K Willemze Rein R Tensen Cornelis P CP

Cancer research 20080401 8

This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combin ...[more]

PMID: 18413736

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Dataset Information

Novel and highly recurrent chromosomal alterations in SÃ©zary syndrome

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Novel and highly recurrent chromosomal alterations in Sézary syndrome.

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