背景神经营养原肌球蛋白受体激酶(NTRK)基因融合在儿童和成人的1%的神经胶质瘤中发现。TRK抑制剂是NTRK融合神经胶质瘤的有希望的治疗剂,因为它们是组织不可知论的并且穿过血脑屏障(BBB)。方法我们调查了来自单个研究所的12个NGS验证的NTRK融合神经胶质瘤,首尔国立大学医院。结果患者队列包括6名儿童(1-15岁)和6名成人(27-72岁)。在十种脑弥漫性低级别和高级别神经胶质瘤中发现了NTRK2融合(DLGs和DHGs,分别),在1例脑增生性婴儿神经节胶质瘤和1例脊髓DHGG中发现了NTRK1融合蛋白。在这个系列中,NTRK2的融合伙伴是HOOK3,KIF5A,GKAP1,LHFPL3,SLMAP,ZBTB43,SPEC1L,FKBP15、KANK1和BCR,而NTRK1融合伴侣是TPR和TPM3。DLGG往往只包含NTRK融合,而DHGG表现出进一步的遗传改变,如TERT启动子/TP53/PTEN突变,CDKN2A/2B纯合缺失,PDGFRA/KIT/MDM4/AKT3扩增,或多重染色体拷贝数畸变。四名患者接受了TRK抑制剂的辅助治疗(larotrectinib,repotrectinib,或entrectinib),其中3人还接受了化疗(n=2)或质子治疗(n=1)。接受TRK抑制剂的患者的治疗结果各不相同:一名接受拉罗列替尼治疗残留DLGG的儿童病情稳定。相比之下,另一名脊髓DHGG患儿经历了多次肿瘤复发.尽管用拉罗列替尼治疗,最终,孩子因肿瘤进展而死亡。一名接受恩替尼治疗的成胶质细胞瘤(GBM)成年患者也经历了肿瘤进展并最终死亡。然而,一位患有DHGG的儿科患者获得了成功的结果,在第二次总肿瘤切除后,再进行repotrectinib治疗,没有显示疾病的证据。该患者先前在初次手术后经历过复发,并接受了卡铂/噻替帕和质子治疗的自体外周血干细胞治疗。结论我们的研究阐明了LGG和HGG与NTRK融合蛋白在病理学和TRK抑制剂反应方面的明显差异。
Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.