Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Neuro Oncol. 2018 Jan 10;20(1):66-77. doi: 10.1093/neuonc/nox132.
Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown.
Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA).
In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA.
Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.
弥漫性低级别胶质瘤（LGG）根据异柠檬酸脱氢酶（IDH）突变状态和 1 号染色体和 19 号染色体（1p/19q）的缺失情况，可分为 3 种不同的亚型。然而，其他遗传病变对生存的亚型特异性影响在很大程度上仍不清楚。
我们使用 Cox 比例风险回归模型，在日本弥漫性低级别胶质瘤患者队列中（完全针对与 LGG 相关的驱动突变和拷贝数变异进行基因分型，n = 308），研究遗传改变和临床病理因素对每个 LGG 亚型生存的亚型特异性影响。使用来自癌症基因组图谱（TCGA）的 414 例 LGG 病例数据集对结果进行验证。
在少突胶质细胞瘤中，IDH 突变和 1p/19q 缺失、NOTCH1 突变（P = 0.0041）和不完全切除（P = 0.0019）与较短的生存时间显著相关。在星形细胞瘤中，IDH 突变、PIK3R1 突变（P = 0.0014）和视网膜母细胞瘤通路基因改变（RB1、CDKN2A 和 CDK4）（P = 0.013）是不良预后的独立预测因素。在 IDH 野生型 LGG 中，7p 增益、10q 缺失、TERT 启动子突变（P = 0.024）和 3 级组织学的共存（P < 0.0001）独立预测预后不良。没有这些因素的 IDH 野生型 LGG 发病年龄更年轻（P = 0.042），并且不太可能具有胶质母细胞瘤的遗传病变特征，与其他 IDH 野生型 LGG 相比，这表明它们可能代表生物学上不同的亚型。这些结果在 TCGA 队列中得到了很大程度的证实。
特定于亚型的遗传病变可用于对每个 LGG 亚型内的患者进行分层，从而实现更好的预后预测和管理。
