Identification of ALK as a major familial neuroblastoma predisposition gene

Yaël P. Mossé, Marci Laudenslager, Luca Longo, Kristina A. Cole, Andrew Wood, Edward F. Attiyeh, Michael J. Laquaglia, Rachel Sennett, Jill E. Lynch, Patrizia Perri, Geneviève Laureys, Frank Speleman, Cecilia Kim, Cuiping Hou, Hakon Hakonarson, Ali Torkamani, Nicholas J. Schork, Garrett M. Brodeur, Gian P. Tonini, Eric RappaportMarcella Devoto, John M. Maris

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)930-935
Number of pages6
JournalNature
Volume455
Issue number7215
DOIs
Publication statusPublished - Oct 16 2008

ASJC Scopus subject areas

  • General

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