Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Neurosurgical Institute of Fudan University, Shanghai, China.
J Neurooncol. 2021 Mar;152(1):27-36. doi: 10.1007/s11060-020-03676-5. Epub 2021 Jan 24.
Glioma is the most common primary brain tumor. Clear classification is crucial for accurate diagnosis and individualized treatment. Histopathological characteristics and genetic alterations have shown to be related to prognosis and treatment response. Germline variants are important components of genetic alterations. However, the distribution of germline variations in glioma patients and their association with survival remain unknown.
We carried out whole-exome sequencing on 99 cases to explore germline variants in glioma. We also analyzed the association of germline variants with clinicopathological features and other prognostic indicators.
All the glioma cases harbored rare germline variants. Germline ALK variants (gALK-Mut) were identified in 12/99 (12.12%) patients. The gALK-Mut patients had significantly shorter overall survival than germline ALK wildtype (gALK-WT) patients in the all glioma group (99 cases) and the subset of patients with IDH-wildtype glioblastoma (IDH-WT-GBM, 39 cases) (P = 0.013 and 0.027, respectively). The gALK-Mut patients also had higher frequency of BIRC5, PIK3CA and RPN1 somatic mutations than the gALK-WT patients in IDH-WT-GBM. Other confounding factors appeared to contribute to patient survival. The subgroup of patients in IDH-WT-GBM with gALK-Mut/TP53-Mut had worse prognosis than the gALK-WT/TP53-Mut subgroup (P = 0.031); The gALK-Mut/TERT-WT and gALK-Mut/TERT-Mut subgroups both had a worse prognosis than the gALK-WT/TERT-Mut subgroup (P = 0.031 and 0.018, respectively).
Our study revealed ALK variation was an independent indicator of poor prognosis in glioma and IDH-WT-GBM. It could be a promising biomarker and tractable therapeutic target for this deadly disease.
神经胶质瘤是最常见的原发性脑肿瘤。准确的诊断和个体化治疗需要对其进行明确的分类。组织病理学特征和遗传改变与预后和治疗反应有关。种系变异是遗传改变的重要组成部分。然而，神经胶质瘤患者的种系变异分布及其与生存的关系尚不清楚。
我们对 99 例病例进行了全外显子组测序，以探讨神经胶质瘤中的种系变异。我们还分析了种系变异与临床病理特征和其他预后指标的关系。
所有神经胶质瘤病例均存在罕见的种系变异。在 99 例患者中，有 12 例（12.12%）患者存在种系 ALK 变异（gALK-Mut）。在所有神经胶质瘤病例组（99 例）和 IDH 野生型胶质母细胞瘤（IDH-WT-GBM，39 例）亚组中，gALK-Mut 患者的总生存期明显短于种系 ALK 野生型（gALK-WT）患者（P=0.013 和 0.027）。在 IDH-WT-GBM 中，gALK-Mut 患者的 BIRC5、PIK3CA 和 RPN1 体细胞突变频率也高于 gALK-WT 患者。其他混杂因素似乎也影响了患者的生存。在 IDH-WT-GBM 中，gALK-Mut/TP53-Mut 亚组患者的预后比 gALK-WT/TP53-Mut 亚组患者差（P=0.031）；gALK-Mut/TERT-WT 和 gALK-Mut/TERT-Mut 亚组患者的预后均比 gALK-WT/TERT-Mut 亚组患者差（P=0.031 和 0.018）。
本研究表明，ALK 变异是神经胶质瘤和 IDH-WT-GBM 患者预后不良的独立指标。ALK 可能是一种很有前途的生物标志物和治疗靶点，为治疗这种致命疾病提供了新的思路。
