Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis
Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis
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DOI：
10.1053/j.gastro.2005.06.060
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发表时间：
2005-09-01
期刊：
影响因子：
29.4
通讯作者：
Longley, BJ
中科院分区：
文献类型：
--
作者：
Hartmann, K;Wardelmann, E;Longley, BJ
胃肠道间质瘤 (GISTS) 通常与激活 KIT 突变相关，影响 KIT 酪氨酸激酶的调节域。成人散发性肥大细胞增多症通常也是由 KIT 突变引起，然而，KIT 突变通过影响分子的细胞内酶位点来激活 KIT。大多数 GISTS 对与酶位点结合的 KIT 抑制剂有反应；然而，在大多数肥大细胞增多症病例中，修饰的酶位点不受这些药物的影响。我们提出了一个同时患有家族性 GISTS 和肥大细胞增多症的亲属，其在外显子 8 中表达一种新的种系 KIT 突变，导致密码子 419 缺失并影响 KIT 的胞外结构域。该突变激活 KIT，突变型 KIT 被酪氨酸激酶抑制剂甲磺酸伊马替尼抑制。我们的研究在 KIT 分子中发现了一个新的调控区域，并强烈表明具有细胞外 KIT 突变的患者对酪氨酸激酶抑制剂有反应。
Gastrointestinal stromal tumors (GISTS) are often associated with activating KIT mutations, affecting regulatory domains of the KIT tyrosine kinase. Sporadic mastocytosis in adults is usually also caused by KIT mutations that, however, activate KIT by affecting the intracellular enzymatic site of the molecule. Most GISTS respond to KIT inhibitors that bind to the enzymatic site; in most cases of mastocytosis, however, the modified enzymatic site is not affected by these drugs. We present a kindred with both familial GISTS and mastocytosis that express a novel germline KIT mutation in exon 8, resulting in deletion of codon 419 and affecting the extracellular domain of KIT. This mutation activates KIT, and the mutant KIT is inhibited by the tyrosine kinase inhibitor imatinib mesylate. Our studies identify a new regulatory region in the KIT molecule and strongly suggest that patients with extracellular KIT mutations respond to tyrosine kinase inhibitors.