title: Anaplastic lymphoma kinase aberrations in rhabdomyosarcoma: clinical and prognostic implications.
abstract: OBJECTIVE
  The aim of this study is to investigate anaplastic lymphoma kinase (ALK) protein expression and underlying genetic aberrations in rhabdomyosarcoma (RMS), with special attention to clinical and prognostic implications.
  
  
  METHODS
  A total of 189 paraffin-embedded RMS tumor specimens from 145 patients were collected on tissue microarray. ALK protein expression was evaluated by immunohistochemistry. ALK gene (2p23) copy number and translocations were determined by in situ hybridization. cDNA sequencing of the receptor tyrosine kinase domain of the ALK gene was assessed in 43 samples.
  
  
  RESULTS
  Strong cytoplasmic ALK protein expression was more frequently observed in alveolar RMS (ARMS) than in embryonal RMS (ERMS) (81% v 32%, respectively; P < .001). ALK gene copy number gain was detected in the vast majority of ARMS (88%), compared with 52% of ERMS (P < .001). ALK copy number correlated with protein expression in primary tumors (n = 107). We identified one point mutation (2%) and seven tumors harboring whole exon deletions (16%). In ERMS, specific ALK gain in the primary tumor correlated with metastatic disease (100% in metastatic disease v 29% in nonmetastatic disease; P = .004) and poor disease-specific survival (5-year disease-specific survival: 62% v 82% for nonspecific or no gain; P = .046).
  
  
  CONCLUSIONS
  Because ALK aberrations on genomic and protein levels are frequently found in RMSs, in particular ARMS, and are associated with disease progression and outcome in ERMS, ALK may play a role in tumor biology and may provide a potential therapeutic target for these tumors. Future research should aim at the oncogenic role of ALK and the potential effect of ALK inhibitors in RMS.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: J Carlijn
authors.initials: JC
authors.lastname: van Gaal
authors.forename: Uta E
authors.initials: UE
authors.lastname: Flucke
authors.forename: Melissa H S
authors.initials: MH
authors.lastname: Roeffen
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Annelies M C
authors.initials: AM
authors.lastname: Mavinkurve-Groothuis
authors.forename: Albert J H
authors.initials: AJ
authors.lastname: Suurmeijer
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Yvonne M H
authors.initials: YM
authors.lastname: Versleijen-Jonkers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D012208:Rhabdomyosarcoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases