title: Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.
abstract: OBJECTIVE
  Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.
  
  
  METHODS
  The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis.
  
  
  RESULTS
  ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival.
  
  
  CONCLUSIONS
  ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Sara
authors: S
authors: De Brouwer
authors: Katleen
authors: K
authors: De Preter
authors: Candy
authors: C
authors: Kumps
authors: Piotr
authors: P
authors: Zabrocki
authors: Michaël
authors: M
authors: Porcu
authors: Ellen M
authors: EM
authors: Westerhout
authors: Arjan
authors: A
authors: Lakeman
authors: Jo
authors: J
authors: Vandesompele
authors: Jasmien
authors: J
authors: Hoebeeck
authors: Tom
authors: T
authors: Van Maerken
authors: Anne
authors: A
authors: De Paepe
authors: Geneviève
authors: G
authors: Laureys
authors: Johannes H
authors: JH
authors: Schulte
authors: Alexander
authors: A
authors: Schramm
authors: Caroline
authors: C
authors: Van Den Broecke
authors: Joëlle
authors: J
authors: Vermeulen
authors: Nadine
authors: N
authors: Van Roy
authors: Klaus
authors: K
authors: Beiske
authors: Marleen
authors: M
authors: Renard
authors: Rosa
authors: R
authors: Noguera
authors: Olivier
authors: O
authors: Delattre
authors: Isabelle
authors: I
authors: Janoueix-Lerosey
authors: Per
authors: P
authors: Kogner
authors: Tommy
authors: T
authors: Martinsson
authors: Akira
authors: A
authors: Nakagawara
authors: Miki
authors: M
authors: Ohira
authors: Huib
authors: H
authors: Caron
authors: Angelika
authors: A
authors: Eggert
authors: Jan
authors: J
authors: Cools
authors: Rogier
authors: R
authors: Versteeg
authors: Frank
authors: F
authors: Speleman
mesh_terms: D019943:Amino Acid Substitution; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005784:Gene Amplification; D020869:Gene Expression Profiling; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases