title: Key roles for MYC, KIT and RET signaling in secondary angiosarcomas.
abstract: BACKGROUND
  Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically indistinguishable primary and secondary angiosarcomas.
  
  
  METHODS
  Whole-genome (18k) c-DNA-mediated annealing, selection, extension and ligation analysis was used to genetically profile 26 primary and 29 secondary angiosarcomas. Key findings were thereafter validated using RT-qPCR, immunohistochemistry and validation of the gene signature to an external data set.
  
  
  RESULTS
  In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas.
  
  
  CONCLUSIONS
  Upregulation of MYC, KIT and RET and downregulation of CDKN2C characterise secondary angiosarcoma, which implies possibilities for diagnostic application and a mechanistic basis for therapeutic evaluation of RET-kinase-inhibitors in these highly aggressive tumours.
authors.affiliation: 1] Department of Orthopedics, Section III, Clinical Sciences, Lund University, 22185 Lund, Sweden [2] Department of Oncology, Section V, Clinical Sciences, Lund University, 22185 Lund, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Styring
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Seinen
authors.affiliation: Department of Oncology, Section V, Clinical Sciences, Lund University, 22185 Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Dominguez-Valentin
authors.affiliation: Department of Pathology, Section V, Clinical Sciences, Lund University, 22185 Lund, Sweden.
authors.forename: H A
authors.initials: HA
authors.lastname: Domanski
authors.affiliation: Department of Oncology, Section V, Clinical Sciences, Lund University, 22185 Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Jönsson
authors.affiliation: Department of Orthopedics, Section III, Clinical Sciences, Lund University, 22185 Lund, Sweden.
authors.forename: F V
authors.initials: FV
authors.lastname: von Steyern
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 Groningen, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoekstra
authors.affiliation: Department of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 Groningen, The Netherlands.
authors.forename: A J H
authors.initials: AJ
authors.lastname: Suurmeijer
authors.affiliation: 1] Department of Oncology, Section V, Clinical Sciences, Lund University, 22185 Lund, Sweden [2] Clinical Research Centre, Hvidovre Hospital, Copenhagen University, 2650 Hvidovre, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Nilbert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc; D015894:Genome, Human; D006394:Hemangiosarcoma / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human