High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis

Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 06/2011; 50(6):397-408. DOI: 10.1002/gcc.20864
Source: PubMed


Pediatric rhabdomyosarcoma occurs as two biologically distinct histological variants, embryonal (ERMS) and alveolar (ARMS). To identify genomic changes that drive ERMS pathogenesis, we used a new array comparative genomic hybridization (aCGH) platform to examine a specific subset of ERMS tumors, those occurring in children with clinically defined intermediate-risk disease. The aCGH platform used has an average probe spacing ∼1 kb, and can identify genomic changes with single gene resolution. Our data suggest that these tumors share a common genomic program that includes inactivation of a master regulator of the p53 and Rb pathways, CDKN2A/B, and activation of FGFR4, Ras, and Hedgehog (Hh) signaling. The CDKN2A/B tumor suppressor is deleted in most patient samples. FGFR4, which encodes a receptor tyrosine kinase, is activated in 20% of tumors, predominantly by amplification of mutant, activating FGFR4 alleles. Over 50% of patients had low-level gains of a region containing the Hh-pathway transcription factor GLI1, and a gene expression pattern consistent with Hh-pathway activation. We also identified intragenic deletions affecting NF1, a tumor suppressor and inhibitor of Ras, in 15% of tumor samples. Deletion of NF1 and the presence of activating Ras mutations (in 42% of patients) were mutually exclusive, suggesting NF1 loss is an alternative and potentially common mechanism of Ras activation in ERMS. Our data suggest that intermediate-risk ERMS is driven by a common set of genomic defects, a finding that has important implications for the application of targeted therapies to improve the treatment of children diagnosed with this disease.

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    • "Most of them exists frequent gains and amplifications. Using an aCGH platform to examine a specific subset of 26 frozen ERMS samples, Vera et al. have found that these tumors share a common genomic program with a high frequency of gains at 12q13.3 (about 50%) in ERMS [26]. In this study, we have observed high frequencies of gains at 12q13.3–q14.1 in RMS (about 60%), in ERMS (60%), and in ARMS (66.67%), respectively. "
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    ABSTRACT: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. The genetic etiology of RMS remains largely unclear underlying its development and progression. To reveal novel genes more precisely and new therapeutic targets associated with RMS, we used high-resolution array comparative genomic hybridization (aCGH) to explore tumor-associated copy number variations (CNVs) and genes in RMS. We confirmed several important genes by quantitative real-time polymerase chain reaction (QRT-PCR). We then performed bioinformatics-based functional enrichment analysis for genes located in the genomic regions with CNVs. In addition, we identified miRNAs located in the corresponding amplification and deletion regions and performed miRNA functional enrichment analysis. aCGH analyses revealed that all RMS showed specific gains and losses. The amplification regions were 12q13.12, 12q13.3, and 12q13.3-q14.1. The deletion regions were 1p21.1, 2q14.1, 5q13.2, 9p12, and 9q12. The recurrent regions with gains were 12q13.3, 12q13.3-q14.1, 12q14.1, and 17q25.1. The recurrent regions with losses were 9p12-p11.2, 10q11.21-q11.22, 14q32.33, 16p11.2, and 22q11.1. The mean mRNA level of GLI1 in RMS was 6.61-fold higher than that in controls (p = 0.0477) by QRT-PCR. Meanwhile, the mean mRNA level of GEFT in RMS samples was 3.92-fold higher than that in controls (p = 0.0354). Bioinformatic analysis showed that genes were enriched in functions such as immunoglobulin domain, induction of apoptosis, and defensin. Proto-oncogene functions were involved in alveolar RMS. miRNAs that located in the amplified regions in RMS tend to be enriched in oncogenic activity (miR-24 and miR-27a). In conclusion, this study identified a number of CNVs in RMS and functional analyses showed enrichment for genes and miRNAs located in these CNVs regions. These findings may potentially help the identification of novel biomarkers and/or drug targets implicated in diagnosis of and targeted therapy for RMS.
    PLoS ONE 04/2014; 9(4):e94924. DOI:10.1371/journal.pone.0094924 · 3.23 Impact Factor
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    • "First, elevated FGFR4 expression in RMS tumors can be a direct result of the PAX3-FOXO1 fusion oncogene, since FGFR4 was reported to be one of the direct targets of the transcription factor [13]. Secondly, up-regulation of FGFR4 expression in RMS can be achieved through localized gene amplification [22]. Thirdly, 7.5% of primary RMS tumors harbor a damaging missense mutation in the tyrosine kinase domain of FGFR4 which results in a constitutively active signaling molecule [9]. "
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    ABSTRACT: Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.
    PLoS ONE 10/2013; 8(10):e76551. DOI:10.1371/journal.pone.0076551 · 3.23 Impact Factor
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    • "In addition, evidence support that Hh signalling is essential for carcinogenesis and spreading of malignant melanoma, ovarian cancer, leukemia and B-cell lymphomas [38-42]. New study showed that over 50% of childhood Embryonal Rhabdomyosarcoma (ERMS) could have Hh signalling activation [43].The majority of these extracutaneous cancers which have Hh signalling dysregulation show ligand dependent abnormalities [22]. Immunohistochemistry analysis of various component of the Hh signalling pathway including SHH, PTCH, SMO, GLI-1, GLI-2 and GLI-3 showed a dramatic overexpression , in skin and head and neck squamous cell carcinomas samples. "
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    ABSTRACT: Hedgehog signalling pathway has not only a critical role in cell proliferation, differentiation and tissue polarity at embryonic period but also has a vital role in stem cell proliferation, tissue healing and carcinogenesis. Recent research has increased our understanding of this pathway and its relation to other signalling pathways. In addition, a large number of studies confirmed the alteration of Hh signalling pathway in various types of human malignancies including basal cell carcinomas, medulloblastomas, lung, gastrointestinal, ovarian, breast, prostate cancers and leukemia. More than 50 small biomolecules have been introduced which have inhibitory effects on Hh signalling pathway. Although, in many tumors some acceptable results have been showed in phase I clinical trial, closer studies are required to improve drug bioavailability, to decrease the side effects and to find the right small molecules for specific types of cancers, considering patients overall benefits as well.
    Iranian Journal of Cancer Prevention 03/2013; Vol 6,(No 1,):36-43.
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