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Analysis of familial and multiple GIST

家族性和多发性 GIST 分析

基本信息

批准号：
14370076
负责人：
HIROTA Seiichi
金额：
$ 7.49万
依托单位：
Hyogo College of Medicine (2004)Osaka University (2002-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370076/
关键词：
GIST Familial and multiple GISTs model mouse knock-in-mouse Imatinib c-kit gene PDGFR alpha von Recklinghausen disease 機能獲得性の突然変異 NF1遺伝子多発性GIST家系 germline c-kit gene mutation NF-1 gene mutation germline 機能獲得性突然変異カハールの介在細胞 /

项目摘要

We found a patient with multiple GISTs(gastrointestinal stromal tumors), and examined his family to clarify whether the cause of multiple GISTs might be derived from germline c-kit mutation. Some members of his family similarly had multiple GISTs, and they had c-kit gene mutation at tyrosine kinase II domain. Proliferation of interstitial cells of Cajal(ICCs) was also seen in the patients as in the cases reported previously. The mutation was proved to be gain-of-function mutation, and is considered to be a cause of multiple GISTs in this family. This family is the first case with germline c-kit gene mutalion at at tyrosine kinase II domain.We further examined the clonality of diffuse proliferation of ICCs in familial GIST patients. The proliferative lesion showed polyclonal nature while each GIST demonstrated to be monoclonal. We also showed that KIT activation by tyrosine kinase II domain mutation was not effectively inhibited by a selective tyrosine kinase inhibitor, Imatinib. The downstream molecules of KIT signal transduction were not also fully inhibited by Imatinib.We investigated the cause of GISTs without c-kit gene mutation. Approximately half of GISTs without c-kit gene mutation had PDGFR alpha gene mutation. Two types of PDGFR alpha gene mutation were seen, and KIT activation by the juxtamembrane domain mutation was effectively inhibited by Imatinib but that by the tyrosine kinase II domain mutation was not. We demonstrated that regrowth of GISTs during the Imatinib treatment (development of resistant clone) was caused by an additional c-kit gene mutation to original c-kit gene mutation. Moreover, we showed that GISTs from neurofibromatosis type1 patients did not have any c-kit gene mutation.

我们发现了一个患有多发性GIST（胃肠道间质瘤）的患者，并检查了他的家人，以澄清多发性GIST的原因是否可能来自生殖系c-kit突变。其家族中部分成员同样存在多发性GIST，且在酪氨酸激酶II结构域存在c-kit基因突变。与先前报道的病例一样，患者中也可见Cajal间质细胞（ICC）增殖。该突变被证实为功能获得性突变，并被认为是该家族多发性GIST的原因。该家系为首例生殖系c-kit基因在酪氨酸激酶II结构域突变的病例，我们进一步研究了家族性GIST患者ICC弥漫性增殖的克隆性。增生性病变表现为多克隆性，而每个GIST表现为单克隆性。我们还表明，KIT激活酪氨酸激酶II结构域突变不能有效地抑制选择性酪氨酸激酶抑制剂，伊马替尼。伊马替尼对KIT信号转导的下游分子也没有完全抑制作用。无c-kit基因突变的GIST中约有一半存在PDGFR α基因突变。观察到两种类型的PDGFR α基因突变，伊马替尼可有效抑制由胞膜结构域突变引起的KIT激活，但不能抑制由酪氨酸激酶II结构域突变引起的KIT激活。我们证明了伊马替尼治疗期间GIST的再生长（耐药克隆的形成）是由原始c-kit基因突变的额外c-kit基因突变引起的。此外，我们发现，GIST从神经纤维瘤病1型患者没有任何c-kit基因突变。