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Identification of ALK as a major familial neuroblastoma predisposition gene

机译：鉴定ALK是主要的家族性神经母细胞瘤易感基因

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Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.
机译：神经母细胞瘤是一种可以遗传的儿童期癌症，但遗传病因学尚不清楚。在这里，我们显示了间变性淋巴瘤激酶（ALK）基因中的种系突变可以解释大多数遗传性神经母细胞瘤，而且激活性突变也可以通过体细胞获得。我们首先在神经母细胞瘤谱系中使用全基因组扫描，在2p23-24染色体带上发现了重要的连锁信号。区域候选基因的重测序确定了ALK酪氨酸激酶结构域中的三个单独的种系错义突变，该突变与该疾病在八个单独的家族中分离。在194个高风险神经母细胞瘤样品中进行的重测序显示，在12.4％的样品中，酪氨酸激酶域中存在体细胞获得性突变。十个突变中的九个映射到激酶结构域的关键区域，并且很有可能被预测为致癌驱动因素。突变导致组成型磷酸化，而定向敲低ALK信使RNA则导致对所有携带突变或扩增的ALK的细胞系以及六个ALK野生型细胞系中的两个细胞生长产生深远的抑制作用。我们的结果表明，ALK的可遗传突变是家族性神经母细胞瘤的主要原因，而这种细胞表面激酶的种系或获得性激活是这种致死性小儿恶性肿瘤的易于治疗的靶标。

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