KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors
KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors
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DOI：
10.1016/s0002-9440(10)64946-2
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发表时间：
2000-03-01
影响因子：
6
通讯作者：
Fletcher, JA
中科院分区：
文献类型：
--
作者：
Lux, ML;Rubin, BP;Fletcher, JA
胃肠道间质瘤（GIST）是胃肠道最常见的间叶肿瘤。GIST表达KIT受体酪氨酸激酶，并且许多病例在KIT质膜区域具有激活突变。我们现在报告的分析KIT的cDNA和基因组序列在8个GIST缺乏质膜区域突变。6例含有杂合子外显子9突变，其中6个核苷酸，编码Ala-Tyr，重复。另外2例病例包含纯合外显子13错义突变，导致Glu取代Lys（642），与组成性KIT酪氨酸磷酸化相关。非肿瘤伴发组织的DNA序列分析显示，外显子9和外显子13突变体。这些是第一次描述，在任何肿瘤中，突变的KIT外显子编码的C-末端的细胞外结构域和第一部分的分裂激酶结构域。这些研究结果表明，KIT可能被激活的突变，在至少三个结构域-细胞外，质膜，激酶-在GIST。
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms arising in the gastrointestinal tract. GISTs express the KIT receptor tyrosine kinase, and many cases have activating mutations in the KIT juxtamembrane region. We now report an analysis of KIT cDNA and genomic sequences in eight GISTs that lack juxtamembrane region mutations. Six cases contained heterozygous exon 9 mutations in which six nucleotides, encoding Ala-Tyr, were duplicated. The other two cases contained homozygous exon 13 missense mutations, resulting in substitution of Glu for Lys(642), that were associated with constitutive KIT tyrosine phosphorylation. Sequence analysis of DNAs from nonneoplastic companion tissues revealed that both the exon 9 and exon 13 mutations were somatic. These are the first descriptions, in any tumor, of mutations in KIT exons encoding the C-terminal end of the extracellular domain and the first part of the split kinase domain. These findings indicate that KIT may be activated by mutations in at least three domains-extracellular, juxtamembrane, and kinase-in GISTs.