TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma
TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma
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DOI：
10.1007/s00401-021-02337-9
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发表时间：
2021-06-20
影响因子：
12.7
通讯作者：
Ichimura, Koichi
中科院分区：
文献类型：
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作者：
Fujimoto, Kenji;Arita, Hideyuki;Ichimura, Koichi
CNS 肿瘤分类学分子和实用方法联盟 (cIMPACT-NOW) 更新 3 建议，组织学 II 级和 III 级 IDH 野生型弥漫性星形细胞胶质瘤，如果存在 EGFR 扩增、整个 7 号染色体增加和整个 10 号染色体丢失 (7 + /10 -) 的组合或 TERT 启动子 (pTERT) 突变，应考虑为 胶质母细胞瘤（GBM），世界卫生组织 IV 级。在这项回顾性研究中，我们检查了基于 pTERT 状态和拷贝数改变 (CNA) 的分子分类在 IDH 野生型低级别胶质瘤（LGG、II 级和 III 级）中的实用性。评估了 pTERT 突变和 CNAs 对生存的影响，包括 EGFR 获得/扩增、PTEN 缺失、CDKN2A 纯合缺失和 PDGFRA 获得/扩增。我们分析了 46 名 IDH 野生型/pTERT 突变 (mut) LGG 患者和 85 名 IDH 野生型/pTERT 野生型 LGG 患者。 pTERT-mut 患者中 EGFR 扩增以及 EGFR 增加和 PTEN 丢失 (EGFR + /PTEN -) 的组合显着更频繁 (p < 0.0001)。 Cox回归分析显示，pTERT突变是不良预后的显着预测因子（风险比[HR] 2.79，95%置信区间[CI] 1.55-4.89，p = 0.0008），但EGFR扩增和EGFR + /PTEN - 都不是IDH野生型LGG的独立预后因素。 PDGFRA 增益/扩增是 IDH 野生型/pTERT 野生型 LGG 中的一个显着不良预后因素（HR 2.44，95% CI 1.09-5.27，p = 0.03，Cox 回归分析）。通过 DNA 甲基化分析，具有 pTERT-mut 或 PDGFRA 扩增的 IDH 野生型 LGG 大部分与 GBM 聚集在一起。因此，我们的研究表明，pTERT 突变状态的分析对于诊断具有胶质母细胞瘤分子特征的 IDH 野生型弥漫性星形细胞胶质瘤是必要且充分的。 PDGFRA 状态可能有助于进一步描述 IDH 野生型/pTERT 野生型 LGG。甲基化分析表明，不具有 GBM 分子特征的 IDH 野生型 LGG 是一组异质性肿瘤。其中一些不属于现有类别，但其预后明显好于 GBM 人群。
The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM.