目的 分析1例长期伊马替尼治疗后多部位、异时性复发病灶敏感/耐药共存的少见胃肠道间质瘤（GISTs）患者的临床资料，揭示GISTs继发突变的异质性是复发耐药过程中的重要属性。 方法 收集1例复发GISTs患者的临床资料，采用HE染色法进行组织学观察，免疫组织化学染色检测相关蛋白表达，一代和二代测序技术分析肿瘤基因变异情况。 结果 患者，男性，66岁，因胃间质瘤行胃部分切除术。一代测序技术检测结果显示为原癌基因，受体酪氨酸激酶（KIT）基因11号外显子缺失突变（p.551-554del）。伊马替尼治疗1年左右，停药4个月后复发，患者出现脾区病灶，继续采用伊马替尼一线治疗，脾区病灶得到控制。59个月后盆腔发现新病灶，采用伊马替尼加量（600 mg·d^－1）并舒尼替尼二线治疗，治疗2个月后CT检查结果显示患者脾区病灶大小趋于稳定，而盆腔新病灶体积持续增大。二代测序技术检测结果显示两复发灶在原有KIT基因11号外显子缺失突变的基础上，分别继发KIT基因13号外显子（p.V654A）和17号外显子（p.Y823D）突变。 结论 GISTs在靶向药物选择作用的压力下，肿瘤生物学行为表现出复杂性，即时间异质性、空间异型性和分子异质性，不同复发灶可以出现不同的耐药机制。

Objective To analyze the clinical data of a rare case of gastrointestinal stromal tumors （GISTs） with multifocal heterochronous primary resistance due to temporal gene mutations after long-term treatment with imatinib， and to reveal the importance of secondary mutation heterogeneity in the recurrence and resistance process of GISTs. Methods The clinical data of one patient with recurrent GISTs were collected. The histomorphology observation was observed by HE staining；the expressions of related proteins were detected by immunohistochemistry；first and second generation sequencing techniques were used to analyze the tumor gene mutations. Results The patient， a 66-year-old male， underwent partial gastrectomy for gastric stromal tumor.The first-generation sequencing results identified it was a proto-oncogenea and there was a deletion mutation in exon 11 of the tyrosine protein kinase kit （KIT） gene （p.551-554del）. Approximately one year after imatinib treatment and a subsequent 4-month drug holiday， the patient experienced a relapse with a splenic lesion.The continuous first-line treatment with imatinib controlled the splenic lesion. After 59 months， a new pelvic mass was identified， and the patient received increased doses of imatinib （600 mg·day^－1） along with second-line therapy with sunitinib. After treated for two months，the CT scan results showed that the size of the splenic lesion tended to stabilize， while the volume of the new pelvic lesion continued to increase. The second generation sequencing results indicated that on the basis of the original KIT gene exon 11 deletion， subsequent mutations in exon 13 （p.V654A） and exon 17 （p.Y823D） of the KIT gene occurred separately in two recurrent lesions. Conclusion Under the pressure of targeted drug selection， the biological behavior of GISTs shows complexity，such as，time heterogeneity，spatial heterogeneity and molecular heterogeneity； different recurrent lesions may exhibit different resistance mechanisms.