title: High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma.
abstract: OBJECTIVE
  Genomic alterations of the anaplastic lymphoma kinase (ALK) gene have been postulated to contribute to neuroblastoma pathogenesis. This study aimed to determine the interrelation of ALK mutations, ALK expression levels, and clinical phenotype in primary neuroblastoma.
  
  
  METHODS
  The genomic ALK status and global gene expression patterns were examined in 263 primary neuroblastomas. Allele-specific ALK expression was determined by cDNA cloning and sequencing. Associations of genomic ALK alterations and ALK expression levels with clinical phenotypes and transcriptomic profiles were compared.
  
  
  RESULTS
  Nonsynonymous point mutations of ALK were detected in 21 of 263 neuroblastomas (8%). Tumors with ALK mutations exhibited about 2-fold elevated median ALK mRNA levels in comparison with tumors with wild-type (WT) ALK. Unexpectedly, the WT allele was preferentially expressed in 12 of 21 mutated tumors. Whereas survival of patients with ALK mutated tumors was significantly worse as compared with the entire cohort of WT ALK patients, it was similarly poor in patients with WT ALK tumors in which ALK expression was as high as in ALK mutated neuroblastomas. Global gene expression patterns of tumors with ALK mutations or with high-level WT ALK expression were highly similar, and suggested that ALK may be involved in cellular proliferation in primary neuroblastoma.
  
  
  CONCLUSIONS
  Primary neuroblastomas with mutated ALK exhibit high ALK expression levels and strongly resemble neuroblastomas with elevated WT ALK expression levels in both their clinical and molecular phenotypes. These data suggest that high levels of mutated and WT ALK mediate similar molecular functions that may contribute to a malignant phenotype in primary neuroblastoma.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.forename: Hagen S
authors.initials: HS
authors.lastname: Bachmann
authors.forename: Bent
authors.initials: B
authors.lastname: Brockmeyer
authors.forename: Katleen
authors.initials: K
authors.lastname: Depreter
authors.forename: André
authors.initials: A
authors.lastname: Oberthür
authors.forename: Sandra
authors.initials: S
authors.lastname: Ackermann
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kahlert
authors.forename: Kristian
authors.initials: K
authors.lastname: Pajtler
authors.forename: Jessica
authors.initials: J
authors.lastname: Theissen
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases