Analysis of thePTCH coding region in human rhabdomyosarcoma

Calzada‐Wack, Julia; Schnitzbauer, Udo; Walch, Axel; Wurster, Karlheinz; Kappler, Roland; Nathrath, Michaela; Hahn, Heidi

doi:10.1002/humu.9056

Cited by 35 publications

(18 citation statements)

References 17 publications

(25 reference statements)

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“…Several studies identified loss of heterozygosity (8-35% of patients) and deletions (33% of patients) in band 9q22, a large region containing PTCH1 and many other genes (Tostar et al, 2005). PTCH1-specific mutations have not been detected in spontaneous RMS tumors (14 sequenced samples) (Calzada-Wack et al, 2002). This finding is surprising given findings in other Hedgehog-associated cancers; 30-40% of basal cell carcinomas and $20% of medulloblastomas Johnson et al, 1996;Wolter et al, 1997;Xie et al, 1997;Lam et al, 1999;Eberhart, 2003) have inactivating mutations in PTCH1.…”

Section: Ink4bmentioning

confidence: 95%

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

Paulson

Chandler

Rakheja

et al. 2011

Genes Chromosomes & Cancer

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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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Section: Ink4bmentioning

confidence: 95%

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

Paulson

Chandler

Rakheja

et al. 2011

Genes Chromosomes & Cancer

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“…44,45 Chromosomal translocations in ARMS lead to the expression of PAX3/FKHR or PAX7/FKHR fusion proteins that correlate with poorer treatment outcomes. 46 Other oncogenes and cell cycle modulators, including TP53 and MDM2, [47][48][49][50][51] cyclin-dependent kinase inhibitor (CDKN)2A, [52][53][54][55] AKT, 56,57 phosphatase and tensin homolog (PTEN), 58,59 survivin, 60,61 RAS, 62 PTCH, [63][64][65] …”

mentioning

confidence: 99%

Mice Lacking Dystrophin or α Sarcoglycan Spontaneously Develop Embryonal Rhabdomyosarcoma with Cancer-Associated p53 Mutations and Alternatively Spliced or Mutant Mdm2 Transcripts

Fernández

Serinagaoglu

Hammond

et al. 2010

The American Journal of Pathology

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Altered expression of proteins in the dystrophin-associated glycoprotein complex results in muscular dystrophy and has more recently been implicated in a number of forms of cancer. Here we show that loss of either of two members of this complex , dystrophin in mdx mice or ␣ sarcoglycan in Sgca ؊/؊ mice , results in the spontaneous development of muscle-derived embryonal rhabdomyosarcoma (RMS) after 1 year of age. Many mdx and Sgca ؊/؊ tumors showed increased expression of insulin-like growth factor 2, retinoblastoma protein , and phosphorylated Akt and decreased expression of phosphatase and tensin homolog gene , much as is found in a human RMS. Further , all mdx and Sgca ؊/؊ RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. The mdx RMS also contained missense mutations in Mdm2 or alternatively spliced Mdm2 transcripts that lacked an exon encoding a portion of the p53-binding domain. No Pax3:Fkhr or Pax7:Fkhr translocation mRNA products were evident in any tumor. Expression of natively glycosylated ␣ dystroglycan and ␣ sarcoglycan was reduced in mdx RMS , whereas dystrophin expression was absent in almost all human RMS , both for embryonal and alveolar RMS subtypes. These studies show that absence of members of the dystrophin-associated glycoprotein complex constitutes a permissive environment for spontaneous development of embryonal RMS associated with mutation of p53 and mutation or altered splicing

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“…Controversially, Calzada et al, did not detect mutations in the coding sequence of PTCH1 in 14 RMS sequenced [47]. This is corroborated by another study showing absence of PTCH1 loss-of-function mutations or SMO amplifications in 26 NRMS examined [41].…”

Section: Role Of Hedgehog Pathway In Rmsmentioning

confidence: 88%

Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

Manzella¹,

Schäfer

2016

CDT

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Rhabdomyosarcoma (RMS) is the most frequent pediatric soft-tissue tumor accounting for about 7% of childhood malignancies. Multimodal therapy is the standard treatment for individuals with RMS but generally fails to cure high-risk group patients and can result in long-term side effects. Therefore, understanding the mechanisms driving RMS might help to find new candidate targets for more specific and effective therapeutic modalities. One of the molecular machineries, which is often deregulated in cancer and specifically involved in the tumorigenesis of RMS, is Hedgehog (Hh) signaling. There is increasing evidence that targeting this developmental pathway may hold promise in future treatment strategies for RMS. In this review, we discuss the contribution of the Hh pathway in RMS, the challenges of inhibiting this embryonic signaling in children with an update on recent preclinical data and ongoing clinical trials.

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Analysis of thePTCH coding region in human rhabdomyosarcoma

Cited by 35 publications

References 17 publications

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

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

Mice Lacking Dystrophin or α Sarcoglycan Spontaneously Develop Embryonal Rhabdomyosarcoma with Cancer-Associated p53 Mutations and Alternatively Spliced or Mutant Mdm2 Transcripts

Interfering with Hedgehog Pathway: New Avenues for Targeted Therapy in Rhabdomyosarcoma

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