1. 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
2. Translational Pediatric Oncology, National Institute for Cancer Research and Italian Neuroblastoma Foundation, National Institute for Cancer Research, Genoa 16132, Italy
3. Advanced Biotechnology Center, Genoa 16132, Italy
4. Center for Medical Genetics, Ghent University Hospital, Gent B-9000, Belgium
5. The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
6. Scripps Genomic Medicine and the Scripps Research Institute, La Jolla, California 92037, USA
7. Division of Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics and CCEB, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
8. University of Rome "La Sapienza", Department of Experimental Medicine, Rome 00161, Italy
9. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Correspondence to: John M. Maris^1,9 Correspondence and requests for materials should be addressed to J.M.M. (Email: maris@chop.edu).

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.

1. 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
2. Translational Pediatric Oncology, National Institute for Cancer Research and Italian Neuroblastoma Foundation, National Institute for Cancer Research, Genoa 16132, Italy
3. Advanced Biotechnology Center, Genoa 16132, Italy
4. Center for Medical Genetics, Ghent University Hospital, Gent B-9000, Belgium
5. The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
6. Scripps Genomic Medicine and the Scripps Research Institute, La Jolla, California 92037, USA
7. Division of Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics and CCEB, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
8. University of Rome "La Sapienza", Department of Experimental Medicine, Rome 00161, Italy
9. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Correspondence to: John M. Maris^1,9 Correspondence and requests for materials should be addressed to J.M.M. (Email: maris@chop.edu).

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