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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。
OBJECTIVE: The application of imatinib has changed the treatment and prognosis of gastrointestinal stromal tumors. The prognosis of patients with advanced gastrointestinal stromal tumors was significantly improved after treatment. However, with the extension of treatment time, the number of patients with drug resistance also gradually increased. Imatinib resistance has become the current research hotspot. The aim of this study was to investigate the mechanism of resistance to imatinib. Methods: By using PCR bi-directional DNA sequencing, 9 patients with imatinib-resistant or stable gastrointestinal stromal tumors were treated with imatinib before and after treatment, and the tumor tissues were subjected to 9 , 11,13,17 exon and 12 and exon 18 of platelet derived growth factor receptor (PDGFR) gene were sequenced. RESULTS: KIT gene-activating mutations were present in 7 of 9 patients, of which 6 occurred in the transmembrane region of exon 11 of KIT gene and the 13th exon in 1 patient. In 4 patients with imatinib secondary drug resistance, a second mutation occurred, showing that the T of exon 17 of KIT gene was replaced by G (T2467G), which resulted in 823 codons encoding amino acids from Tyrosine to aspartic acid. CONCLUSION: Secondary resistance to imatinib may be related to T replaced by G at codon 2467 of exon 17 of KIT gene (T2467G).