TERT promoter mutations in a cohort of adult gliomas –Clinicopathological correlates

Purpose: This study characterizes diffuse gliomas (WHO grade II, III and IV) to determine the frequency of telomerase reverse transcriptase promoter (TERTp) mutations, association of TERTp mutations with other molecular alterations and to assess the role of TERTp mutation in overall survival and progression free survival in relation to histological and molecular glioma subtypes.

Methods: This study analyzed a cohort of 107 adult patients with diffuse gliomas, WHO grades II and III and glioblastoma, by immunohistochemistry for isocitrate dehydrogenase (IDH) and alpha-thalassemia/mental retardation, X-linked (ATRX) mutations, fluorescence in situ hybridization (FISH) for 1p/19q co-deletions and polymerase chain reaction (PCR) sequencing for TERTp mutation. Further, five glioma molecular sub-groups were derived using three molecular alterations and included the sub-groups with: i) IDH mutations only, ii) IDH and TERTp mutation only, iii) IDH and 1p/19q co-deletion only, iv) Triple negative and v) Triple positive.
Results: IDH mutations and 1p/19q co-deletions were individually and significantly associated with an improved progression free (p=0.001 and p=0.002 respectively) and overall survival (p=0.000 and p=0.005 respectively) in the present cohort of gliomas. TERTp mutations occurred frequently in anaplastic oligodendrogliomas (94%), oligodendrogliomas (87.5%) and glioblastomas (54%). Sub-division into molecular sub-groups showed that the triple positive tumors carried the best prognosis, followed by IDH only, triple negative and finally the TERTp mutation only tumors (p-value <0.000).
Conclusion: This indicates that sub-classification using these molecular markers separates tumors into prognostically relevant categories.

目的：本研究旨在对弥漫性胶质瘤（世界卫生组织分级II、III和IV级）进行特征描述，以确定端粒酶反转录酶启动子（TERTp）突变的频率，探究TERTp突变与其他分子改变的关联，并评估TERTp突变在总生存期和无进展生存期中的作用，以及与组织学和分子胶质瘤亚型的关系。

方法：本研究通过对107例成人弥漫性胶质瘤患者（世界卫生组织分级II和III级及胶质母细胞瘤）进行免疫组化检测异柠檬酸脱氢酶（IDH）和α-地贫/智力障碍、X连锁（ATRX）突变，荧光原位杂交（FISH）检测1p/19q共缺失，以及聚合酶链式反应（PCR）测序检测TERTp突变进行分析。此外，通过三种分子改变衍生出五种胶质瘤分子亚组，包括仅含IDH突变、仅含IDH和TERTp突变、仅含IDH和1p/19q共缺失、三阴性以及三阳性亚组。

结果：在本组胶质瘤患者中，IDH突变和1p/19q共缺失分别与显著提高的无进展生存期（p=0.001和p=0.002）和总生存期（p=0.000和p=0.005）相关。TERTp突变在化生性少突胶质瘤（94%）、少突胶质瘤（87.5%）和胶质母细胞瘤（54%）中较为常见。分子亚组的进一步分析表明，三阳性肿瘤预后最佳，其次是仅含IDH突变、三阴性，最后是仅含TERTp突变肿瘤（p值<0.000）。

结论：这表明，利用这些分子标志物进行亚型分类可以将肿瘤分为具有预后意义的类别。