1. Institut Curie, Centre de Recherche,
2. Inserm, U830, 26 rue d'Ulm, Paris F-75248, France
3. Institut Gustave Roussy, Département de pédiatrie, 39 rue Camille Desmoulins, 94805 Villejuif, France
4. Institut Curie, Unité de Génétique Somatique, Paris F-75248, France
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
6. Centre Léon Bérard, FNCLCC, Laboratoire de Recherche Translationnelle
7. Inserm, U590,
8. Université de Lyon, Lyon1, Institut des Sciences Pharmaceutiques et Biologiques, Lyon F-69008, France
9. Institut Curie, Département de Pédiatrie, Paris F-75248, France
10. Service de Génétique, CHU de Rouen et Inserm U614, Faculté de Médecine et de Pharmacie, 76183 Rouen Cedex, France

Correspondence to: Olivier Delattre^1,2,4 Correspondence and requests for materials should be addressed to O.D. (Email: olivier.delattre@curie.fr).

Abstract

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood^{1, 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 gene^{1, 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 treatments^{6, 7}.

1. Institut Curie, Centre de Recherche,
2. Inserm, U830, 26 rue d'Ulm, Paris F-75248, France
3. Institut Gustave Roussy, Département de pédiatrie, 39 rue Camille Desmoulins, 94805 Villejuif, France
4. Institut Curie, Unité de Génétique Somatique, Paris F-75248, France
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
6. Centre Léon Bérard, FNCLCC, Laboratoire de Recherche Translationnelle
7. Inserm, U590,
8. Université de Lyon, Lyon1, Institut des Sciences Pharmaceutiques et Biologiques, Lyon F-69008, France
9. Institut Curie, Département de Pédiatrie, Paris F-75248, France
10. Service de Génétique, CHU de Rouen et Inserm U614, Faculté de Médecine et de Pharmacie, 76183 Rouen Cedex, France

Correspondence to: Olivier Delattre^1,2,4 Correspondence and requests for materials should be addressed to O.D. (Email: olivier.delattre@curie.fr).

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