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1.
Cancer Genet ; 205(7-8): 391-404, 2012.
Article in English | MEDLINE | ID: mdl-22868000

ABSTRACT

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples, which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7-10% of clinically diagnosed ES tumors in three separate cohorts (University of Utah [N = 40], Children's Oncology Group [N = 31], and University of Michigan [N = 55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P < 0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk stratification in future clinical trials.


Subject(s)
Bone Neoplasms/genetics , Gene Dosage , Molecular Probes , Sarcoma, Ewing/genetics , Adolescent , Adult , Bone Neoplasms/pathology , Cell Adhesion Molecules, Neuronal/genetics , Child , Child, Preschool , Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Extracellular Matrix Proteins/genetics , Female , Gene Deletion , Humans , Immunohistochemistry , Infant , Loss of Heterozygosity , Male , Nerve Tissue Proteins/genetics , Paraffin Embedding , Reelin Protein , SMARCB1 Protein , Sarcoma, Ewing/pathology , Serine Endopeptidases/genetics , Transcription Factors/genetics , Young Adult
2.
Front Oncol ; 1: 39, 2011.
Article in English | MEDLINE | ID: mdl-22655244

ABSTRACT

The glutathione S-transferases (GSTs) are a family of ubiquitously expressed polymorphic enzymes important for detoxifying endogenous and exogenous compounds. In addition to their classic activity of detoxification by conjugation of compounds with glutathione, many other functions are now found to be associated with GSTs. The associations between GST polymorphisms/functions and human disease susceptibility or treatment outcome, mostly in adults, have been extensively studied and reviewed. This mini review focuses on studies related to GST epidemiology and functions related to pediatric cancer. Opportunities to exploit GST in pediatric cancer therapy are also discussed.

3.
Cancer Res ; 69(23): 9047-55, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19920188

ABSTRACT

Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in-frame, to the DNA-binding domain-containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a corepressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. Although the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1 and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for the development of Ewing's sarcoma because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma.


Subject(s)
Cell Transformation, Neoplastic/genetics , DAX-1 Orphan Nuclear Receptor/genetics , Gene Expression Regulation, Neoplastic , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Protein c-fli-1/genetics , Sarcoma, Ewing/genetics , Cell Line, Tumor , Chromatin/genetics , Chromatin/metabolism , DAX-1 Orphan Nuclear Receptor/metabolism , Down-Regulation , Humans , Oncogene Proteins, Fusion/metabolism , Proto-Oncogene Protein c-fli-1/metabolism , RNA-Binding Protein EWS , Sarcoma, Ewing/metabolism , Transcription, Genetic , Up-Regulation
4.
Proc Natl Acad Sci U S A ; 105(29): 10149-54, 2008 Jul 22.
Article in English | MEDLINE | ID: mdl-18626011

ABSTRACT

The ETS gene family is frequently involved in chromosome translocations that cause human cancer, including prostate cancer, leukemia, and sarcoma. However, the mechanisms by which oncogenic ETS proteins, which are DNA-binding transcription factors, target genes necessary for tumorigenesis is not well understood. Ewing's sarcoma serves as a paradigm for the entire class of ETS-associated tumors because nearly all cases harbor recurrent chromosomal translocations involving ETS genes. The most common translocation in Ewing's sarcoma encodes the EWS/FLI oncogenic transcription factor. We used whole genome localization (ChIP-chip) to identify target genes that are directly bound by EWS/FLI. Analysis of the promoters of these genes demonstrated a significant over-representation of highly repetitive GGAA-containing elements (microsatellites). In a parallel approach, we found that EWS/FLI uses GGAA microsatellites to regulate the expression of some of its target genes including NR0B1, a gene required for Ewing's sarcoma oncogenesis. The microsatellite in the NR0B1 promoter bound EWS/FLI in vitro and in vivo and was both necessary and sufficient to confer EWS/FLI regulation to a reporter gene. Genome wide computational studies demonstrated that GGAA microsatellites were enriched close to EWS/FLI-up-regulated genes but not down-regulated genes. Mechanistic studies demonstrated that the ability of EWS/FLI to bind DNA and modulate gene expression through these repetitive elements depended on the number of consecutive GGAA motifs. These findings illustrate an unprecedented route to specificity for ETS proteins and use of microsatellites in tumorigenesis.


Subject(s)
Microsatellite Repeats , Oncogene Proteins, Fusion/genetics , Response Elements , Sarcoma, Ewing/genetics , Transcription Factors/genetics , Base Sequence , Cell Line, Tumor , Chromatin Immunoprecipitation , DNA, Neoplasm/genetics , Humans , Molecular Sequence Data , Proto-Oncogene Protein c-fli-1 , RNA-Binding Protein EWS , Transfection
5.
Mol Cancer Res ; 4(11): 851-9, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17114343

ABSTRACT

A number of solid tumors, such as alveolar rhabdomyosarcoma, synovial sarcoma, and myxoid liposarcoma, are associated with recurrent translocation events that encode fusion proteins. Ewing's sarcoma is a pediatric tumor that serves as a prototype for this tumor class. Ewing's sarcomas usually harbor the (11;22)(q24;q12) translocation. The t(11;22) encodes the EWS/FLI fusion oncoprotein. EWS/FLI functions as an aberrant transcription factor, but the key target genes that are involved in oncogenesis are largely unknown. Although some target genes have been defined, many of these have been identified in heterologous model systems with uncertain relevance to the human disease. To understand the function of EWS/FLI and its targets in a more clinically relevant system, we used retroviral-mediated RNAi to "knock-down" the fusion protein in patient-derived Ewing's sarcoma cell lines. By combining transcriptional profiling data from three of these lines, we identified a conserved transcriptional response to EWS/FLI. The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. NR0B1 is a developmentally important orphan nuclear receptor with no previously defined role in oncogenesis. We validated NR0B1 as an EWS/FLI-dysregulated gene and confirmed its expression in primary human tumor samples. Functional studies revealed that ongoing NR0B1 expression is required for the transformed phenotype of Ewing's sarcoma. These studies define a new role for NR0B1 in oncogenic transformation and emphasize the utility of analyzing the function of EWS/FLI in Ewing's sarcoma cells.


Subject(s)
Bone Neoplasms/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Genes, Neoplasm , Oncogene Proteins, Fusion/physiology , Receptors, Retinoic Acid/genetics , Repressor Proteins/genetics , Sarcoma, Ewing/genetics , Transcription Factors/physiology , Animals , Bone Neoplasms/pathology , DAX-1 Orphan Nuclear Receptor , Gene Expression Profiling , Humans , Mice , Oncogene Proteins, Fusion/antagonists & inhibitors , Oncogene Proteins, Fusion/genetics , Phenotype , Proto-Oncogene Protein c-fli-1 , RNA Interference , RNA-Binding Protein EWS , Retroviridae/genetics , Sarcoma, Ewing/pathology , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics
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