Analysis of familial and multiple GIST

我们发现了一位患有多发性胃肠道间质瘤的患者，并对其家人进行了检查，以明确多发性胃肠道间质瘤的病因是否可能来自种系c-kit突变。他的家族成员也有类似的多发性gist，他们在酪氨酸激酶II结构域有c-kit基因突变。与先前报道的病例一样，在患者中也观察到Cajal间质细胞（ICCs）的增殖。该突变被证明是功能获得突变，并被认为是该家族多发gist的原因。该家族是首例在酪氨酸激酶II结构域发生种系c-kit基因突变的病例。我们进一步研究了家族性GIST患者ICCs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。我们还发现，选择性酪氨酸激酶抑制剂伊马替尼不能有效抑制酪氨酸激酶II结构域突变引起的KIT激活。KIT信号转导的下游分子也未被伊马替尼完全抑制。我们探讨无c-kit基因突变的gist病因。无c-kit基因突变的gist患者约有一半存在PDGFR α基因突变。PDGFR α基因突变有两种类型，伊马替尼可有效抑制近膜结构域突变对KIT的激活，而酪氨酸激酶II结构域突变对KIT的激活没有抑制作用。我们证明，在伊马替尼治疗期间，gist的再生（耐药克隆的发展）是由原始c-kit基因突变引起的额外c-kit基因突变。此外，我们发现来自1型神经纤维瘤病患者的gist没有任何c-kit基因突变。

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.