神经母细胞瘤是最常见的小儿癌症。这种疾病有一个强烈的家族联系，而且30年以前科学家就曾预测，这种疾病有一个遗传元素。
现在，四个研究小组报告，他们在神经母细胞瘤患者的酪氨酸受体ALK（(anaplastic lymphoma kinase）中发现了多种突变。ALK充当神经母细胞瘤的一种易患基因，而且体细胞点突变是在零星的神经母细胞瘤病例中出现的。这些突变有助于提高ALK的激酶活性，在体内可改变细胞和显示致瘤活性。ALK抑制药物可抑制神经母细胞瘤细胞的增殖，所以有可能用作抗癌药物。（生物谷 Bioon.com）
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Nature vol.455 (7215), (16 Oct 2008)
Identification of ALK as a major familial neuroblastoma predisposition gene
Yaël P. Mossé1, Marci Laudenslager1, Luca Longo2, Kristina A. Cole1, Andrew Wood1, Edward F. Attiyeh1, Michael J. Laquaglia1, Rachel Sennett1, Jill E. Lynch1, Patrizia Perri2,3, Geneviève Laureys4, Frank Speleman4, Cecilia Kim5, Cuiping Hou1,5, Hakon Hakonarson5,7, Ali Torkamani6, Nicholas J. Schork6, Garrett M. Brodeur1, Gian P. Tonini2, Eric Rappaport1, Marcella Devoto7,8 & John M. Maris1,9
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.
