Identification of ALK as a major familial neuroblastoma predisposition gene.
Identification of ALK as a major familial neuroblastoma predisposition gene.
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DOI：
10.1038/nature07261
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发表时间：
2008-10-16
期刊：
影响因子：
64.8
通讯作者：
Maris, John M.
中科院分区：
文献类型：
--
作者：
Mosse, Yael P.;Laudenslager, Marci;Longo, Luca;Cole, Kristina A.;Wood, Andrew;Attiyeh, Edward F.;Laquaglia, Michael J.;Sennett, Rachel;Lynch, Jill E.;Perri, Patrizia;Laureys, Genevieve;Speleman, Frank;Kim, Cecilia;Hou, Cuiping;Hakonarson, Hakon;Torkamani, Ali;Schork, Nicholas J.;Brodeur, Garrett M.;Tonini, Gian P.;Rappaport, Eric;Devoto, Marcella;Maris, John M.
尽管化疗强度急剧增加，儿童癌症神经母细胞瘤的存活率并没有实质性的提高。像大多数人类癌症一样，这种胚胎恶性肿瘤可以遗传，但家族性和零星发生的神经母细胞瘤的遗传病因在很大程度上是未知的。在这里，我们发现间变性淋巴瘤激酶基因（ALK）的种系突变解释了大多数遗传性神经母细胞瘤，激活突变也可以通过身体获得。我们首先通过对神经母细胞瘤家系进行全基因组扫描，在2号染色体短臂处发现了一个显著的连锁信号（rs1344063处最大非参数LOD=4.23）。区域候选基因重测序发现ALK的酪氨酸激酶结构域（G1128A， R1192P和R1275Q）有三个不同的错义突变，这些突变在8个不同的家族中与疾病分离。对491例零星发生的人类神经母细胞瘤样本的检查显示，22.8%的人获得了ALK位点，另外3.3%的人高度扩增，这些畸变与疾病死亡高度相关（P=0.0003）。194个高危神经母细胞瘤样本的重测序显示12.4%的人在酪氨酸激酶结构域内发生了体细胞获得性突变。十个突变中的九个映射到激酶结构域的关键区域，并且被预测为高概率的致癌驱动因素。突变导致与激活一致的组成性磷酸化，并且靶向敲低ALK mRNA导致4个携带突变或扩增ALK的细胞系中的4个以及6个ALK野生型细胞系中的2个的生长受到严重抑制。我们的研究结果表明，ALK的遗传突变是家族性神经母细胞瘤的主要原因，并且这种细胞表面激酶的种系或获得性激活是这种致命的儿科恶性肿瘤的一个可处理的治疗靶点。
Survival rates for the childhood cancer neuroblastoma have not substantively improved despite dramatic escalation in chemotherapy intensity. Like most human cancers, this embryonal malignancy can be inherited, but the genetic etiology of familial and sporadically occurring neuroblastoma was largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase gene (ALK) explain the majority of hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at the short arm of chromosome 2 (maximum nonparametric LOD=4.23 at rs1344063) using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate missense mutations in the tyrosine kinase domain of ALK (G1128A, R1192P and R1275Q) that segregated with the disease in eight separate families. Examination of 491 sporadically occurring human neuroblastoma samples showed that the ALK locus was gained in 22.8%, and highly amplified in an additional 3.3%, and that these aberrations were highly associated with death from disease (P=0.0003). Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations within the tyrosine kinase domain in 12.4%. Nine of the ten mutations map to critical regions of the kinase domain and were predicted to be oncogenic drivers with high probability. Mutations resulted in constitutive phosphorylation consistent with activation, and targeted knockdown of ALK mRNA resulted in profound growth inhibition of 4 of 4 cell lines harboring mutant or amplified ALK, as well as 2 of 6 wild type for ALK. Our results demonstrate that heritable mutations of ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this cell surface kinase is a tractable therapeutic target for this lethal pediatric malignancy.
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影响因子：
3.7
作者：
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通讯作者：
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