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Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

Nature volume 455, pages 967–970 (2008)Cite this article

Abstract

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood1,2. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene1,2,3,4. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK)5 tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments6,7.

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Figure 1: Genetic characteristics of ALK in neuroblastoma.
Figure 2: Functional characterization of mutated ALK.

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Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) public database. The accession numbers for gene expression profiles of neuroblastoma samples and SNP data for case NB-99 displayed in Fig. 1c are GSE12460 and GSE12461, respectively.

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Acknowledgements

We are grateful to F. Moreau-Gachelin, I. Gallais, D. Surdez, F. Tirode, A. Fix, F. Bourdeaut, A. Almeida, C. Lucchesi, S. Roman Roman, B. Bressac, J. Bénard and G. Vassal for their critical help. We thank C. Decraene, D. Gentien and B. Albaud from the translational department of Institut Curie for profiling the paediatric tumours, and P. Rosa and E. Barillot for the development of bioinformatic tools. We thank M. Lathrop and the Centre National de Génotypage for the Affymetrix 100K SNP analysis and A. Chompret for collecting families. This work was supported by grants from the Agence Nationale pour la Recherche, the Institut National du Cancer, the Ligue Nationale contre le Cancer (Equipe labellisée and CIT project), the APAESIC (Association des Parents et des Amis des Enfants Soignés à l’Institut Curie), the Association Hubert Gouin, les amis de Claire, Les Bagouz à Manon and Enfance et Santé. A.P. and V.C. are supported by the Comité de l'Ain of the Ligue Nationale contre le Cancer.

Author Contributions I.J.-L., D.L., A.R., L.P., V.C. and V.R. generated the data; I.J.-L., G.P., A.P., J.M., J.A., S.L. and O.D. made the study design and follow-up; L.B., V.C., A.P., G.S., D.V.-C., T.F., S.L. and J.A. contributed biological materials that were used in this study.

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Authors and Affiliations

  1. Institut Curie, Centre de Recherche,,

    Isabelle Janoueix-Lerosey, Delphine Lequin, Virginie Raynal, Gudrun Schleiermacher & Olivier Delattre

  2. Inserm, U830, 26 rue d’Ulm, Paris F-75248, France ,

    Isabelle Janoueix-Lerosey, Delphine Lequin, Virginie Raynal, Gudrun Schleiermacher & Olivier Delattre

  3. Département de pédiatrie, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France,

    Laurence Brugières & Dominique Valteau-Couanet

  4. Institut Curie, Unité de Génétique Somatique, Paris F-75248, France

    Agnès Ribeiro, Gaëlle Pierron & Olivier Delattre

  5. Département de Génétique, Université Paris Descartes, Faculté de Médecine et INSERM-U781, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France,

    Loïc de Pontual, Stanislas Lyonnet & Jeanne Amiel

  6. Centre Léon Bérard, FNCLCC, Laboratoire de Recherche Translationnelle,

    Valérie Combaret & Alain Puisieux

  7. Inserm, U590,,

    Alain Puisieux

  8. Université de Lyon, Lyon1, Institut des Sciences Pharmaceutiques et Biologiques, Lyon F-69008, France ,

    Alain Puisieux

  9. Département de Pédiatrie, Institut Curie, Paris F-75248, France

    Gudrun Schleiermacher & Jean Michon

  10. Service de Génétique, CHU de Rouen et Inserm U614, Faculté de Médecine et de Pharmacie, 76183 Rouen Cedex, France

    Thierry Frebourg

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  1. Isabelle Janoueix-Lerosey
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Correspondence to Olivier Delattre.

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Janoueix-Lerosey, I., Lequin, D., Brugières, L. et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455, 967–970 (2008). https://doi.org/10.1038/nature07398

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