Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors
Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors
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DOI：
10.1038/labinvest.2011.165
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发表时间：
2012-03
影响因子：
5
通讯作者：
Mayumi Nakai;Y. Hashikura;Mizuka Ohkouchi;M. Yamamura;T. Akiyama;K. Shiba;Noriko Kajimoto;Y. Tsukamoto;H. Hao;K. Isozaki;T. Hirai;S. Hirota
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文献类型：
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作者：
Mayumi Nakai;Y. Hashikura;Mizuka Ohkouchi;M. Yamamura;T. Akiyama;K. Shiba;Noriko Kajimoto;Y. Tsukamoto;H. Hao;K. Isozaki;T. Hirai;S. Hirota
我们在一例68岁女性多发性胃肠道间质瘤（GIST）患者中发现c-kit基因第11外显子的一种新型种系突变，导致c-kit基因产物第553位密码子Tyr被Cys取代（KIT-Tyr 553 Cys）。在本研究中，我们进行了突变分析，在她的家庭成员，以确定载体和特征的突变，通过引入相应的突变（鼠KIT-Tyr 552 Cys）到表达载体具有小鼠c-kit cDNA。对其家庭成员外周血白细胞的突变分析显示，一名44岁的儿子也有同样的突变，但目前他既没有明显的症状，也没有多发性GIST的影像。通过用具有鼠突变c-kit cDNA的表达载体转染，白细胞介素-3依赖性Ba/F3鼠淋巴样细胞在没有任何生长因子的情况下开始自主生长，表明该突变被认为是功能获得性的。小分子酪氨酸激酶抑制剂伊马替尼可有效抑制KIT-Tyr 552 Cys的自磷酸化。KIT抑制剂的另一种小分子尼洛替尼也能有效抑制KIT-Tyr 552 Cys的自磷酸化。事实上，伊马替尼和尼洛替尼均有效抑制表达KIT-Tyr 552 Cys的Ba/F3细胞的增殖。这些结果表明，新型人类KIT-Tyr 553 Cys突变是目前家族性和多发性GIST的原因，伊马替尼和尼洛替尼都可能有效抑制该家族患者中发生的GIST的生长。
We found a novel type germline mutation at exon 11 of the c-kit gene, which results in a substitution of Tyr to Cys at codon 553 of the c-kit gene product (KIT-Tyr553Cys), in a 68-year-old female patient with multiple gastrointestinal stromal tumors (GISTs). In the present study, we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation (murine KIT-Tyr552Cys) into expression vector possessing murine c-kit cDNA. Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44-year-old son had the same mutation, but at present he had neither apparent symptoms nor images of multiple GISTs. By transfection with the expression vector possessing the murine mutant c-kit cDNA, interleukin-3-dependent Ba/F3 murine lymphoid cells started growing autonomously without any growth factors, indicating that the mutation was considered to be of gain-of-function. Imatinib, a small molecule of tyrosine kinase inhibitor, effectively inhibited autophosphorylation of KIT-Tyr552Cys. Nilotinib, another small molecule of the KIT inhibitor, also effectively inhibited autophosphorylation of KIT-Tyr552Cys. In fact, proliferation of Ba/F3 cells expressing KIT-Tyr552Cys was effectively inhibited by both imatinib and nilotinib. These findings indicate that the novel type human KIT-Tyr553Cys mutation is the cause of the present familial and multiple GISTs, and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family.