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

机译：神经母细胞瘤中ALK激酶受体的体细胞和种系激活突变

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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 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.
机译：神经母细胞瘤是一种起源于周围交感神经系统的肿瘤，是儿童期1-2中最常见的实体瘤之一。它通常偶尔发生，但观察到家族性病例，其中一部分与先天性神经c畸形有关的病例与PHOX2B基因的种系突变有关。在这里，我们对一系列神经母细胞瘤进行了全基因组比较基因组杂交分析。反复观察到编码间变性淋巴瘤激酶（ALK）酪氨酸激酶受体的基因座拷贝数增加。一个特别有用的案例显示了严格限于ALK的高级基因扩增，表明该基因可能对神经母细胞瘤的发展有贡献。通过随后对细胞系和原发性肿瘤DNA的直接测序，我们鉴定了主要聚集在两个热点中的ALK激酶结构域的体细胞突变。在两个神经母细胞瘤家族中观察到种系突变，表明ALK是神经母细胞瘤的易感基因。突变的ALK蛋白被过度表达，过度磷酸化并显示出组成型激酶活性。在ALK突变的细胞中，以及在过表达野生型ALK的细胞系中，ALK表达的敲低导致细胞增殖的明显减少。总而言之，这些数据表明ALK是神经母细胞瘤发展中的关键角色，因此可能代表该疾病中非常有吸引力的治疗靶标，而该疾病在目前的治疗中仍然经常致命。

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