Activating c-kit gene mutations in human germ cell tumors
Activating c-kit gene mutations in human germ cell tumors
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DOI：
10.1016/s0002-9440(10)65419-3
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发表时间：
1999-06-01
影响因子：
6
通讯作者：
Moskaluk, CA
中科院分区：
文献类型：
--
作者：
Tian, QS;Frierson, HF;Moskaluk, CA
C-kit基因编码一种酪氨酸激酶受体(KIT)，这是正常精子发生所必需的，在精原细胞瘤和无性细胞瘤中表达，这是人类生殖细胞肿瘤(GCTS)的一个子集。为了确定在GCTS中是否存在c-kit基因的激活突变，采用聚合酶链式反应扩增和DNA测序的方法检测了33例睾丸和卵巢肿瘤组织中膜旁和磷酸转移酶区域的突变。在精原细胞瘤/无性细胞瘤分化的肿瘤中发现一个新的错义突变(D816H)。这些患者非肿瘤组织中的c-kit等位基因为野生型，提示突变等位基因是在癌变过程中获得和选择的。在细胞转染实验中，D816H突变蛋白是一种结构性激活的蛋白，并在酪氨酸残基上被结构性磷酸化。这是首次在GCTS中发现激活的c-kit突变，证明KIT信号转导通路在精原细胞瘤分化的肿瘤发病机制中起重要作用。
The c-kit gene encodes a tyrosine kinase receptor (KIT) that is required in normal spermatogenesis and is expressed in seminomas and dysgerminomas, a subset of human germ cell tumors (GCTs). To determine whether activating mutations of the c-kit gene occur in GCTs, primary tissue samples of 33 testicular and ovarian tumors were examined for mutations in the juxtamembrane and phosphotransferase domains by polymerase chain reaction amplification and DNA sequencing. A novel missense mutation (D816H) was found in the phosphotransferase domain in tumors of seminoma/dysgerminoma differentiation. The c-kit alleles in nonneoplastic tissues from these patients were wild type, suggesting that the mutant alleles were acquired and selected for during malignant transformation. In cell transfection experiments, the D816H mutant protein was a constitutively activated kinase and was constitutively phosphorylated on tyrosine residues. This is the first description of an activating c-kit mutation in GCTs and is evidence that the KIT signal transduction pathway Is important in the pathogenesis of neoplasms with seminoma differentiation.