PDGFRA基因突变型胃肠间质瘤患者生物学特点及预后的分析

Analysis of biological characteristics and prognosis on gastrointestinal stromal tumor with PDGFRA gene mutation

目的 探讨PDGFRA基因突变类型胃肠间质瘤(GIST)的生物学行为特点及生存情况,并了解伊马替尼对其的疗效及生存预后分析.方法 从2003—2018年在北京大学肿瘤医院接受治疗的1 163例GIST患者数据库中筛选出PDGFRA D842V及非D842V突变的患者,并收集患者性别、年龄、肿瘤大小、核分裂相、原发部位、转移部位,以及CD117、CD34、DOG-1表达情况等.并进行生物学特征、临床疗效及预后评价.采用Fisher确切概率法对两组间临床特征分类变量进行分析,Kaplan-Meier法分析PDGFRA突变类型GIST不同亚型患者总生存及无复发生存.结果 共筛选出27例PDGFRA基因突变患者,其中D842V突变率为1.6%(19/1 163);非D842V突变率为0.7%(8/1 163). D842V突变男性患者11例,女性患者8例,男女比例为1.38∶1.00,中位年龄为56(35~72)岁.非D842V突变男性患者4例,女性患者4例,男女比例为1∶1,中位年龄为52(34~82)岁.D842V突变原发灶分别为胃18例、胃肠外1例.非D842V突变原发灶分别为胃6例、空回肠1例、结直肠1例. PDGFRA突变GIST核分裂相<5/50 HPF的比例为63.0%(17/27),19例D842V突变患者中,11例核分裂相<5/50 HPF,3例核分裂相 >10/50 HPF,5例为5~10/50 HPF;8例非D842V突变患者中,6例核分裂相<5/50 HPF,2例为5~10/50 HPF. D842V突变患者中,15例患者CD117检测为阳性(15/19);17 例患者行 CD34 检测,阳性 16 例;DOG-1 阳性者共 15例.非D842V突变患者中, 7 例患者 CD117 检测为阳性( 7/8 ) ;仅 5 例患者进行 CD34 检测,阳性5例(5/5);仅3例患者进行DOG-1检测,阳性3例(3/3).D842V突变患者R0根治术后3年无复发生存率为 51.9%,非D842V 突变患者 3 年无复发生存率为 62.5% ,两组间差异无统计学意义(P=0.380). D842V突变患者在接受伊马替尼辅助治疗后无复发率并未下降,进展期患者伊马替尼一线治疗获益率为0.结论 PDGFRA基因突变率较低,多来源于胃GIST. D842V与非D842V突变呈惰性生物学行为,D842V突变GIST对伊马替尼原发耐药,而非D842V突变GIST可以从伊马替尼治疗中获益.

Objective To investigate the biological behavior characteristics of gastrointestinal stromal tumors (GIST) with PDGFRA mutation and the patients′ survival, and elucidate the efficacy of imatinib therapy. Methods Patients with PDGFRA D842V and non-D842V mutations were screened from a database of 1163 patients with GIST who were treated at Peking University Cancer Hospital from 2003 to 2018. Clinicopathological data of these patients were collected, including gender, age, tumor size, mitotic phase, primary position, metastatic site, and expressions of CD117, CD34, DOG-1. The association of gene mutations with biological behavior of GIST, prognosis of patients, and efficacy of imatinib therapy was examined. Fisher′s exact test was used to compare the clinical characteristics of the two groups. Kaplan-Meier method was used to analyze overall survival and recurrence-free survival. Results A total of 27 patients with PDGFRA mutations were screened, among whom the D842V mutation was 1.6% (19/1 163), and the rate of non-D842V mutation was 0.7% (8/1 163). There were 11 male patients and 8 female patients of D842V mutation with male to female ratio of 1.38∶1 and median age of 56 (35-72) years. There were 4 male patients and 4 female patients of non-D842V mutations with male to female ratio of 1∶1 and median age of 51.5 (34-82) years. The primary lesions of D824V mutation were located in stomach for 18 cases and in parenteral area for 1 case. The primary lesions of non-D842V mutation were located in stomach for 6 cases, in jejunoileum for 1 case and in colorectum for 1 case. The proportion of nuclear fission <5/50 HPF in PDGFRA mutation GIST was 17/27. Among D842V mutation patients, mitotic phase <5/50 HPF accounted for 11/19, mitotic phase >10/50 HPF accounted for 3/19, and 5-10/50 HPF accounted for 5/19. Among non-D842V mutation patients, mitotic phase <5/50 HPF accounted for 6/8, 5-10/50 HPF accounted for 2/8. Of D842V mutation patients, positive CD117 was found in 15 cases (15/19);positive DOG-1 was found in 15 cases (15/19); positive CD34 was found in 16/17 cases. Among patients with non-D842V mutation, 7 patients were positive for CD117(7/8); only 5 patients were tested for CD34, and all 5 patients were positive (5/5); only 3 patients were tested for DOG-1, and all 3 cases were positive (3/3). The 3-year recurrence-free survival rate after radical resection in D842V mutation patients was 51.9% , and that in non-D842V mutation patients was 62.5% without significant difference (P=0.380). Recurrence-free rate did not decreased in patients with D842V mutation after adjuvant imatinib treatment and the benefit rate of first-line treatment with imatinib in patients with advanced disease was zero. Conclusions The PDGFRA gene mutation rate is low, mostly derived from gastric GIST. D842V and non-D842V mutations present inert biological behavior. D842V mutation GIST is resistant to imatinib, and non-D842V mutation GIST can obtain benefit from imatinib treatment.