H3K27变异型弥漫性中线胶质瘤临床病理分析及NTRK作为治疗靶点的初步探讨

Clinicopathological characteristics of H3K27-altered diffuse midline glioma and evaluation of NTRK as its therapeutic target

目的分析H3K27变异型弥漫性中线胶质瘤(diffuse midline glioma,H3K27-altered,DMG)的临床病理学特征及预后相关因素,并探讨神经营养原肌球蛋白受体激酶(neurotrophic tropomyosin receptor kinase,NTRK)作为DMG的治疗靶点的可行性。方法收集2016年7月至2021年3月首都医科大学三博脑科医院诊断为DMG的病例样本232例,分析其临床、影像、病理、O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)启动子甲基化比率、NTRK免疫表达、NTRK基因融合的特点,并对肿瘤发生年龄、部位、组织学分级、NTRK蛋白及基因改变、术后辅助治疗方式在预后方面的意义进行研究。结果232例病例(包含原发/复发病例8例,即共有224例患者,男性118例,女性106例),儿童组(≤18岁)98例,成人组(>18岁)126例。儿童组和成人组发病部位分别以脑干(59/98,60.2%)和丘脑(41/126,32.5%)最为多见。影像学上病变多呈现为T1低或等信号,T2高信号,增强信号变化较大,但多数肿瘤无明显增强信号。组织学分级包含2级(9/224,4.0%)、3级(41/224,18.3%)、4级(174/224,77.7%)。肿瘤细胞均弥漫表达H3K27M,而H3K27me3均表达丢失。MGMT启动子甲基化比率较低(1/45,2.2%)。Pan-TRK蛋白阳性率为79.0%(177/224),NTRK1融合阳性率10.0%(5/50)。儿童组和成人组的组织学分级、NTRK蛋白表达、NTRK基因融合比率差异均无统计学意义(P>0.05)。随访患者159例,其中109例死亡(68.6%),总体生存时间1~55个月,中位生存期12个月。患者预后与年龄、部位、手术方式及术后辅助治疗相关(P<0.05)。结论DMG患者临床预后凶险,成人组和儿童组DMG肿瘤的发病部位、预后存在差异。NTRK1基因融合在DMG中占比达10.0%,提示TRK抑制剂可以作为DMG治疗的一个新选择。

Objective To investigate the clinicopathological characteristics of H3K27-altered diffuse midline glioma(DMG),and to analyze DMG′s prognostic factors,and subsequently,to study the possibility of using NTRK as a therapeutic target for DMG.Methods A total of 232 DMG diagnosed at the Sanbo Brain Hospital,Capital Medical University,Beijing,China from July 2016 to March 2021 were collected.Their clinical,radiological and pathological features,the ratio of MGMT promoter methylation,expression of NTRK,and characteristics of NTRK gene fusion were analyzed.The prognostic values of different factors were also studied,including age,tumor location,histological grade,gene and protein expression of NTRK,and postoperative adjuvant therapy.Results Among the 232 DMG cases,there were 8 patients with both primary and relapse tumors on the record.Thus,a total of 224 patients were analyzed,including 118 males and 106 females.There were 126 adults(>18 years of age)and 98 children(≤18 years of age).Notably,the most frequent location was thalamus(41/126,32.5%)in adults,but brainstem(59/96,60.2%)in children.The lesions showed T1 hypointensity or isointensity,and T2 hyperintensity.However,contrast enhancement patterns of the tumors varied,with many tumors lacking contrast-enhancing.The histological grades included grade 2(9/224,4.0%),grade 3(41/224,18.3%)and grade 4(174/224,77.7%).Two hundred and twenty-four DMGs were diffusely positive for H3K27M and negative for H3K27me3.The ratio of MGMT promoter methylation was low(1/45,2.2%).One hundred and seventy-seven of the 224 cases(177/224,79.0%)were positive for NTRK.Fifty cases were analyzed using fluorescence in situ hybridization.Among them,five DMGs(positive rate,10.0%)were NTRK fusion positive.This study showed that there were no differences between adult and pediatric DMGs in histological grading,expression of NTRK,and NTRK gene fusion.One hundred and fifty-nine patients were included in the follow-up analysis(P>0.05).During the follow-up period,109/159 patients(69.6%)died of the disease,with a median survival time of 12 months(range 1 to 55 months).Univariate log-rank analysis showed that age,location,surgical procedure and postoperative adjuvant therapy were associated with overall survivals of the DMG patients(P<0.05).Conclusions The prognosis of DMG is poor overall.There are differences between adult and pediatric DMGs in anatomic location and prognosis,but not in other features.NTRK1 gene fusion is detected in 10.0%of the tumors.It suggests that TRK inhibitor might be a choice for treating DMG.