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

来自 EBSCO

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作者：

I Janoueix-Lerosey，D Lequin，L Brugieres，Agnes Ribeiro，Loiec de Pontual，Valerie Combaret，V Raynal，A Puisieux，G Schleiermacher，Gaeelle Pierron

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摘要：

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. 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. 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) 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.

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关键词：

Humans Cell Line Neuroblastoma Nucleic Acid Hybridization Phosphorylation Gene Dosage Germ-Line Mutation Point Mutation Cell Division Protein-Tyrosine Kinases