【摘要】 目的:伊马替尼的应用改变了胃肠间质瘤的治疗方式和预后前景,晚期胃肠间质瘤患者治疗后的预后显著提高。然而随着治疗时间的延长,出现耐药的患者人数也逐渐增多。伊马替尼耐药已成为当前的研究热点。本研究旨在探讨伊马替尼的耐药机制。方法:应用PCR双向DNA测序法,对9例伊马替尼耐药或达到疾病稳定的胃肠间质瘤手术患者,在给予伊马替尼治疗前、后,对肿瘤组织进行KIT基因第9、11、13、17外显子以及血小板源性生长因子受体(platelet derived growth factor receptor,PDGFR)基因第12和18外显子的测序分析。结果:9例患者中有7例存在KIT基因激活性突变,其中6例发生KIT基因第11外显子编码的跨膜区突变,1例发生第13外显子突变。4例伊马替尼继发耐药患者均发生二次突变,表现为KIT基因第17外显子密码子第2467位点的T为G所替换(T2467G),可导致823密码子编码氨基酸由酪氨酸转变为天冬氨酸。结论:伊马替尼继发耐药可能与KIT基因第17外显子密码子第2467位点T为G所替换(T2467G)相关。更多还原

【Abstract】 Objective:The application of the tyrosine kinase inhibitor imatinib changed the treatment style and the prognosis foreground of gastrointestinal stromal tumor (GIST). The prognosis of advanced GIST was improved significantly. However, the number of patients with imatinib resistance increased continuously with enlongation of treatment period. Imatinib resistance became a hot point recently. This study aimed to explore the mechanism responsible for the acquired resistance to imatinib. Methods: With the bidirectional DNA sequencing and the analysis of an ABI PRISM 310 capillary electrophoresis system, this work sequenced the extrons 9, 11, 13, and 17 of KIT gene and the extron 12 and 18 in platelet derived growth factor receptor (PDGFR)α gene in the 9 GIST patients who were resistant to imatinib or obtained stable disease (SD) during imatinib treatment. Results: Activating mutations of KIT gene existed in 7 of 9 cases of GIST patients. Six cases had the KIT gene mutation in exon 11 encoding the juxtamembrane domain and 1 case had mutation in exon 13. Secondary KIT mutations were identified in the 4 imatinib-resistant patients. This work found an identical novel missense mutation in exon 17, T2467T→T2467G, which caused a substitution of Tyr by Asp at codon 823 (Y823 D) in tyrosine kinase domain of KIT. Conclusion: The imatinib resistance may be related with missense mutation in exon 17, T2467T→T2467G, in tyrosine kinase domain of KIT.更多还原