Relationship Between <i>MYCN</i> Copy Number and Expression in Rhabdomyosarcomas and Correlation With Adverse Prognosis in the Alveolar Subtype

Williamson, Daniel; Lu, Yong‐Jie; Gordon, Tony; Sciot, Raf; Kelsey, Anna; Fisher, Cyril; Poremba, Christopher; Anderson, John; Pritchard‐Jones, Kathy; Shipley, Janet

doi:10.1200/jco.2005.11.078

Cited by 108 publications

(95 citation statements)

References 20 publications

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“…1). A correlation between the MYCN copy number and immunohistochemical scores was significant in ARMS and ERMS samples (c 2 test for trend, P ¼ 0.039 and P < 0.0001, respectively), and in ARMS, the frequency of amplification was 25%, similar to that previously reported by us and others (3,5). Fusion gene-positive ARMS were associated with higher N-Myc expression than ERMS (c 2 test for trend, P < 0.00005) and higher expression was associated with poorer clinical outcome in patients with ARMS (log-rank test, P ¼ 0.012, n ¼ 48) by Kaplan-Meier analysis but was not significant within fusion positive (log-rank test, P ¼ 0.07, n ¼ 39) or ERMS cases (log-rank test, P ¼ 0.52, n ¼ 149).…”

Section: Resultssupporting

confidence: 88%

“…MYCN gene amplification is most widely known for its association with poor outcome in neuroblastomas (2), although other pediatric tumors including rhabdomyosarcomas (RMS) have been described with MYCN amplification (3)(4)(5). RMS are the most frequent soft tissue sarcomas in children with two main histologic subtypes, embryonal (ERMS) and alveolar (ARMS).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Tonelli

McIntyre

Camerin

et al. 2012

Clinical Cancer Research

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Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription.Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined.Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity.Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo. Clin Cancer Res; 18(3); 796-807. Ó2011 AACR.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Tonelli

McIntyre

Camerin

et al. 2012

Clinical Cancer Research

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“…Rhabdomyosarcoma samples were collected and stored; their pathology was reviewed as previously described (12). The study of rhabdomyosarcoma had both local and national ethical approval (Local Research Ethics Committee No.…”

Section: Methodsmentioning

confidence: 99%

Role for Amplification and Expression of Glypican-5 in Rhabdomyosarcoma

et al. 2007

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Overexpression of genes, through genomic amplification and other mechanisms, can critically affect the behavior of tumor cells. Genomic amplification of the 13q31-32 region is reported in many tumors, including rhabdomyosarcomas that are primarily pediatric sarcomas resembling developing skeletal muscle. The minimum overlapping region of amplification at 13q31-32 in rhabdomyosarcomas was defined as containing two genes: Glypican-5 (GPC5) encoding a cell surface proteoglycan and C13orf25 encompassing the miR-17-92 micro-RNA cluster. Genomic copy number and gene expression analyses of rhabdomyosarcomas indicated that GPC5 was the only gene consistently expressed and up-regulated in all cases with amplification. Constitutive overexpression and knockdown of GPC5 expression in rhabdomyosarcoma cell lines increased and decreased cell proliferation, respectively. A correlation between expression levels of nascent pre-rRNA and GPC5 (P = 0.001), but not a C13orf25 transcript containing miR-17-92, in primary samples supports an association of GPC5 with proliferative capacity in vivo. We show that GPC5 increases proliferation through potentiating the action of the growth factors fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and Wnt1A. GPC5 enhanced the intracellular signaling of FGF2 and HGF and altered the cellular distribution of FGF2. The mesoderm-inducing effect of FGF2 and FGF4 in Xenopus blastocysts was also enhanced. Our data are consistent with a role of GPC5, in the context of sarcomagenesis, in enhancing FGF signaling that leads to mesodermal cell proliferation without induction of myogenic differentiation. Furthermore, the properties of GPC5 make it an attractive target for therapeutic intervention in rhabdomyosarcomas and other tumors that amplify and/or overexpress the gene. [Cancer Res 2007;67(1):57-65]

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“…The cut-off threshold value employed for copy number gain was 1.5 (the equivalent of 3 copies in a diploid cell). 17 Fluorescence In Situ Hybridization. Dual-color fluorescence in situ hybridization (FISH) analysis was performed according as previously described.…”

Section: Methodsmentioning

confidence: 99%

Identification ofPFTAIREprotein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells

Pang

Bai

et al. 2007

Hepatology

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Metastasis is a major cause of cancer morbidity and mortality in individuals with hepatocellular carcinoma (HCC), yet little is known about the underlying molecular basis. Using genetic information derived from chromosome-based comparative genomic hybridization, we have reported previously on regional chromosome 7q21-q22 gains in close association with HCC progression. In this study, we undertook cDNA microarray-based comparative genomic hybridization, to examine the 7q21-q22 region for the involved gene(s) in HCC. High-resolution mapping analysis highlighted 7 candidates, namely PFTAIRE protein kinase 1 (PFTK1), ODAG, CDK6, CAS1, PEX1, SLC25A, and PEG10, within the region. H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide 1 and the third most common cause of cancer-related mortality. One of the reasons for this high mortality is that the tumour usually presents at a stage when curative surgery is no longer feasible because of intrahepatic or extrahepatic metastases. Although the 5-year survival of HCC patients who have undergone hepatectomy has improved in recent years, postoperative intrahepatic recurrence can still be as high as 43% by 2 years after resection, 2 presumably because of preexisting micro-metastases. 3 These observations underscore the urgent need to understand the molecular characteristics and related biological mechanisms in tumor cell dissemination.Despite extensive studies, the underlying genomic alterations in HCC remain poorly understood, 4-6 and few tumor suppressors or proto-oncogenes have been related to metastasis and recurrences. Utilizing genetic information derived from a cohort of 100 HCC tumors analyzed by chromosome-based comparative genomic hybridization (CGH), our group has previously shown several regional chromosome gains, especially over-representations

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Relationship Between MYCN Copy Number and Expression in Rhabdomyosarcomas and Correlation With Adverse Prognosis in the Alveolar Subtype

Abstract: MYCN deregulation is a feature of rhabdomyosarcoma tumorigenesis, defines groups of patients with a poor prognosis, and is a potential target for novel therapies.

Cited by 108 publications

References 20 publications

Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Role for Amplification and Expression of Glypican-5 in Rhabdomyosarcoma

Identification ofPFTAIREprotein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells

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