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

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Abstract
Neuroblastoma is the most common childhood cancer. There is a strong familial association and it was predicted over 30 years ago that there was a genetic element to the disease. Four groups now report the identification of mutations in the tyrosine kinase receptor ALK (anaplastic lymphoma kinase) in neuroblastoma patients. ALK acts as a neuroblastoma predisposition gene, and somatic point mutations occur in sporadic neuroblastoma cases. These mutations promote ALK's kinase activity and can transform cells and display tumorigenic activity in vivo. ALK inhibitors decrease neuroblastoma cell proliferation, so have potential as anticancer drugs. This is one of four papers in this issue that identifies mutations in the tyrosine kinase receptor ALK in neuroblastoma, the most frequent childhood cancer. ALK is found to be a neuroblastoma predisposition gene and somatic points mutations were found in sporadic cases of neuroblastoma. These mutations lead the ALK kinase activation and are able to transform cells and display tumourigenic activity in vivo. ALK inhibitors decrease neuroblastoma cell proliferating and are potential anti-cancer drugs for the treatment of neuroblastoma. 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.