目的:探讨具有n KIT/PDGFRA基因“纯合性”突变胃肠间质瘤（GIST）患者的临床病理特征、靶向药物治疗效果及预后。n 方法:采用回顾性队列研究和倾向性评分匹配方法。“纯合性”突变定义为应用一代测序法检测GIST的n KIT/PDGFRA基因的状态时，表现为测序图中只有突变型基因序列，缺乏野生型序列或突变型基因序列的峰高远高于野生型基因序列（>3倍）；“杂合性”突变定义为在测序图中表现为突变型基因序列与野生型基因序列同时存在，且峰高相近（≤3倍）。收集2008年1月至2021年5月上海4家医院[上海交通大学医学院附属仁济医院（70例）、复旦大学附属中山医院（14例）、海军军医大学附属长海医院（6例）、上海交通大学医学院附属瑞金医院（2例）]确诊为GIST并具有n KIT/PDGFRA基因“纯合性”突变的92例患者的临床病理资料及随访信息。排除围手术期死亡、合并其他恶性肿瘤以及临床病理资料不完整的患者。观察分析患者的临床病理特征和靶向药物治疗效果，疗效评价采用Choi标准，分为肿瘤完全缓解（CR）、部分缓解（PR）、稳定病变（SD）和肿瘤进展（PD）。纳入同期经过手术完整切除的n KIT基因11外显子“杂合性”突变高危GIST患者230例，以及应用伊马替尼（IM）治疗的复发或转移性“杂合性”n KIT基因11外显子突变GIST病例117例，采用倾向评分匹配法，将n KIT基因11外显子“杂合性”突变与“纯合性”突变的GIST患者组成1∶1配对进行生存分析，比较经手术完整切除的两组高危GIST患者的无病生存期（DFS），以及复发或转移性的两组GIST患者的无进展生存期（PFS）。n 结果:在92例具有n KIT/PDGFRA基因“纯合性”突变的GIST病例中，男性58例，女性34例，发病中位年龄62（31~91）岁；原发性GIST 83例。原发高危GIST（53例）、转移性GIST（21例）及复发性GIST（9例）占比90.2%（83/92）。n KIT基因“纯合性”突变有90例（88例外显子11，1例外显子13，1例外显子17），n PDGFRA基因“纯合性”突变2例（分别为外显子12和外显子18）。全组中位随访时间49（8~181）个月。在经手术完整切除的61例原发局限性GIST中，2例为中危GIST、5例为低危GIST、1例为极低危GIST，其中1例中危GIST术后加用了1年IM辅助治疗，随访期间均未出现肿瘤复发；其余53例为高危GIST，50例获得随访资料，其中22例在随访期间出现肿瘤复发。在9例直接采用新辅助靶向治疗（IM或阿伐替尼）的病例中，有5例具有完整影像学随访资料，患者的疗效评价均达到过PR。在所有92例具有n KIT/PDGFRA基因“纯合性”突变的GIST病例中，50例（54.4%）伴有肿瘤转移或在随访期间出现肿瘤复发或进展，12例（13.0%）因肿瘤死亡。匹配后的生存分析显示：在100例手术完整切除的高危GIST中，n KIT基因11外显子“纯合性”突变的GIST比n KIT基因11外显子“杂合性”突变的GIST的DFS更短（中位DFS：72个月比148个月，n P=0.015）；在60例复发或转移性的具有n KIT基因11外显子突变的GIST中，“纯合性”突变的GIST比“杂合性”突变的GIST的PFS更短（中位PFS：38个月比69个月，n P=0.044），差异均具有统计学意义（n P 3 times). “Heterozygous mutation” was defined as the mutant gene sequences coexisted with wild type gene sequences, and the peak height was similar (3 times or less). The clinicopathological data and follow-up information of 92 GIST patients withn KIT/PDGFRA “homozygous mutation” were collected from 4 hospitals in Shanghai from January 2008 to May 2021 (Renji Hospital, Shanghai Jiaotong University School of Medicine: 70 cases; Zhongshan Hospital, Fudan University: 14 cases; Changhai Hospital, Naval Military Medical University: 6 cases and Ruijin Hospital, Shanghai Jiaotong University School of Medicine: 2 cases). Patients with perioperative death, other malignancies, and incomplete clinicopathological information were excluded. The clinicopathological features of the patients and the efficacy of targeted drug therapy were observed and analyzed. The efficacy was evaluated using Choi criteria, which were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition, a total of 230 patients with high-risk GIST with “heterozygous mutation” in exon 11 of n KIT gene and 117 patients with recurrent or metastatic GIST with “heterozygous mutation” in exon 11 of n KIT gene were included. The propensity score matching method was used to match GIST patients with “heterozygous” and “homozygous” mutations in exon 11 of n KIT gene (1∶1) for survival analysis. The disease-free survival (DFS) between two groups of high-risk GIST patients who underwent complete surgical resection were compared. And progression-free survival (PFS) in patients with recurrent or metastatic GIST were compared.n Results:Of the 92 GIST cases with n KIT/PDGFRA “homozygous mutation”, 58 were males and 34 were females, with a median onset age of 62 (31-91) years. Primary GIST 83 cases. Primary high-risk GIST (53 cases), metastatic GIST (21 cases) and recurrent GIST (9 cases) accounted for 90.2% (83/92). There were 90 cases of n KIT gene“homozygous mutation” (exon 11 for 88 cases, exon 13 for 1 case, exon 17 for 1 case), and 2 cases of n PDGFRA gene “homozygous mutation” (exon 12 for 1 case, exon 18 for 1 case). The median follow-up time was 49 (8-181) months. Among the 61 cases of primary localized GIST undergoing complete surgical resection, 2 cases were intermediate-risk GIST, 5 cases were low-risk GIST, and 1 case was very low-risk GIST, of whom 1 case of intermediate-risk GIST received 1-year adjuvant imatinib mesylate (IM) therapy after operation, and no tumor recurrence developed during the follow-up period. The remaining 53 cases were high-risk GIST, and follow-up data were obtained from 50 cases, of whom 22 developed tumor recurrence during follow-up. Of 9 patients directly receiving neoadjuvant targeted therapy (IM or avapritinib), 5 had complete imaging follow-up data, and the evaluation of efficacy achieved PR. Of all the 92 GIST cases with n KIT/PDGFRA “homozygous mutation”, 50 (54.4%) had tumor metastasis or tumor recurrence or progression during follow-up, and 12 (13.0%) died of the tumor. Survival analysis combined with propensity score showed that in 100 cases of high-risk GISTs with complete resection, GISTs with “homozygous mutation” in exon 11 of n KIT gene had shorter disease-free survival (DFS) than GISTs with “heterozygous mutation” in exon 11 of n KIT gene (median DFS: 72 months vs. 148 months, n P=0.015). In 60 cases of recurrent or metastatic GISTs with n KIT gene exon 11 mutation, IM was used as the first-line treatment, and the progression-free survival (PFS) of GISTs with “homozygous mutation” was shorter compared to GISTs with “heterozygous mutation” (median PFS: 38 months vs. 69 months, n P=0.044). The differences were statistically significant.n Conclusions:“Homozygous mutation” in n KIT/PDGFRA gene is associated with the progression of GIST. The corresponding targeted therapeutic drugs are still effective for GIST with n KIT/PDGFRA gene “homozygous mutation”. Compared with GIST patients with “heterozygous mutation” in n KIT exon 11, GIST patients with “homozygous mutation” in n KIT exon 11 are more likely to relapse after surgery and to develop resistance to IM. Therefore, it is still necessary to seek more effective treatment methods for this subset of cases.n