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 Rappaport, Marcella Devoto and John M. Maris ()
Additional contact information
Yaël P. Mossé: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Marci Laudenslager: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Luca Longo: Translational Pediatric Oncology, National Institute for Cancer Research and Italian Neuroblastoma Foundation, National Institute for Cancer Research
Kristina A. Cole: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Andrew Wood: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Edward F. Attiyeh: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Michael J. Laquaglia: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Rachel Sennett: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Jill E. Lynch: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Patrizia Perri: Translational Pediatric Oncology, National Institute for Cancer Research and Italian Neuroblastoma Foundation, National Institute for Cancer Research
Geneviève Laureys: Center for Medical Genetics, Ghent University Hospital
Frank Speleman: Center for Medical Genetics, Ghent University Hospital
Cecilia Kim: The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Cuiping Hou: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Hakon Hakonarson: The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Ali Torkamani: Scripps Genomic Medicine and the Scripps Research Institute, La Jolla, California 92037, USA
Nicholas J. Schork: Scripps Genomic Medicine and the Scripps Research Institute, La Jolla, California 92037, USA
Garrett M. Brodeur: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Gian P. Tonini: Translational Pediatric Oncology, National Institute for Cancer Research and Italian Neuroblastoma Foundation, National Institute for Cancer Research
Eric Rappaport: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Marcella Devoto: The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
John M. Maris: Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Nature, 2008, vol. 455, issue 7215, 930-935

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07261

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