title: Characterization of genetic lesions in rhabdomyosarcoma using a high-density single nucleotide polymorphism array.
abstract: Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes, embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited near-diploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Riki
authors.initials: R
authors.lastname: Nishimura
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hanada
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kato
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002648:Child; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D005784:Gene Amplification; D018628:Gene Dosage; D053673:Glypicans / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics
chemical_list: C106228:GPC5 protein, human; D053673:Glypicans; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins