title: Identification of ALK as a major familial neuroblastoma predisposition gene.
abstract: Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.
authors: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors: Yaël P
authors: YP
authors: Mossé
authors: Marci
authors: M
authors: Laudenslager
authors: Luca
authors: L
authors: Longo
authors: Kristina A
authors: KA
authors: Cole
authors: Andrew
authors: A
authors: Wood
authors: Edward F
authors: EF
authors: Attiyeh
authors: Michael J
authors: MJ
authors: Laquaglia
authors: Rachel
authors: R
authors: Sennett
authors: Jill E
authors: JE
authors: Lynch
authors: Patrizia
authors: P
authors: Perri
authors: Geneviève
authors: G
authors: Laureys
authors: Frank
authors: F
authors: Speleman
authors: Cecilia
authors: C
authors: Kim
authors: Cuiping
authors: C
authors: Hou
authors: Hakon
authors: H
authors: Hakonarson
authors: Ali
authors: A
authors: Torkamani
authors: Nicholas J
authors: NJ
authors: Schork
authors: Garrett M
authors: GM
authors: Brodeur
authors: Gian P
authors: GP
authors: Tonini
authors: Eric
authors: E
authors: Rappaport
authors: Marcella
authors: M
authors: Devoto
authors: John M
authors: JM
authors: Maris
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases