少突胶质细胞瘤、异柠檬酸脱氢酶（IDH）突变型、1p/19q共缺失型和端粒酶逆转录酶启动子（TERTp）野生型的独特分子特征及预后：年轻患者的1级少突胶质细胞瘤？

Distinct molecular profile and outcome of oligodendroglioma, IDH-mutant, 1p/19q-codeleted and TERTp-wildtype: a grade 1 oligodendroglioma of young patients?

作者信息

Nozzoli Filippo, Rahmanzade Ramin, Schmid Simone, Schweizer Leonille, Schrimpf Daniel, Friedel Dennis, Göbel Kirsten, Reuss David E, Banan Rouzbeh, Sievers Philipp, Pusch Stefan, Bogumil Henri, Hinz Felix, Suwala Abigail K, Aras Fuat Kaan, Friedrich Lukas, Osella-Abate Simona, Ricci Alessia Andrea, Macciotta Alessandra, Simon Thorsten, Fleischhack Gudrun, Keyvani Kathy, Hansford Jordan R, Khuong-Quang Dong-Anh, Schucht Philippe, Maragkou Theoni, Juratli Tareq A, Meinhardt Matthias, Zechel Sabrina, Stadelmann Christine, Coras Roland, Sakowitz Oliver W, Goeppert Benjamin, Schittenhelm Jens, Etminan Nima, Ratliff Miriam, Herold-Mende Christel, Pfister Stefan M, Wick Wolfgang, Krieg Sandro M, von Deimling Andreas, Sahm Felix, Bertero Luca

机构信息

Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.

Histopathology and Molecular Diagnostics, Careggi University Hospital, Florence, Italy.

出版信息

Neuro Oncol. 2025 Jul 19. doi: 10.1093/neuonc/noaf141.

DOI:10.1093/neuonc/noaf141

PMID:40692489

Abstract

BACKGROUND

Oligodendrogliomas, characterized by isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletion, often exhibit telomerase reverse transcriptase promoter (TERTp) mutations which have been linked to telomere maintenance (TM) and tumour proliferation. Although there are a few reports on a TERTp-wildtype subset of these tumours in adolescents and young adults, the frequency, molecular characteristics and prognostic implications of TERTp-wildtype status in oligodendrogliomas remains elusive.

METHODS

We retrospectively analysed 166 IDH-mutant and 1p/19q-codeleted oligodendroglioma cases through comprehensive histopathological review and molecular analyses, including Sanger sequencing, DNA methylation profiling and whole exome sequencing (WES).

RESULTS

A TERTp-wildtype status was observed in 20/166 cases (12.0%) and was significantly associated with noticeably young age (p<0.001), CNS WHO grade 2 (p=0.003), and the absence of additional DNA copy number variations (CNVs) beyond the pathognomonic 1p/19q codeletion (p<0.001). Epigenetic profiling demonstrated TERTp-wildtype tumours shaped a distinct subgroup at the utmost periphery of TERTp-mutant oligodendrogliomas. Methylation analysis of the upstream and proximal TERTp regions revealed that, in line with the absence of genetic alterations, epigenetic regulation does not favour TERT overexpression in TERTp-wildtype oligodendrogliomas. WES showed no TM-related genes alterations in TERTp-wildtype cases. Cox regression analysis confirmed TERTp-wildtype status as an independent prognostic factor for more favourable progression-free survival (PFS) (p=0.009).

CONCLUSIONS

In conclusion, "oligodendroglioma, IDH-mutant, 1p/19q-codeleted and TERTp-wildtype" represents a distinct molecular subgroup associated with younger age and a better clinical course compared to CNS WHO grade 2 oligodendrogliomas.

摘要

背景

少突胶质细胞瘤以异柠檬酸脱氢酶（IDH）突变和1p/19q共缺失为特征，常表现出端粒酶逆转录酶启动子（TERTp）突变，这些突变与端粒维持（TM）和肿瘤增殖有关。尽管有一些关于青少年和年轻成人中这些肿瘤的TERTp野生型亚组的报道，但少突胶质细胞瘤中TERTp野生型状态的频率、分子特征和预后意义仍不清楚。

方法

我们通过全面的组织病理学检查和分子分析，包括桑格测序、DNA甲基化谱分析和全外显子测序（WES），对166例IDH突变和1p/19q共缺失的少突胶质细胞瘤病例进行了回顾性分析。

结果

166例病例中有20例（12.0%）观察到TERTp野生型状态，且与明显年轻的年龄（p<0.001）、中枢神经系统WHO 2级（p=0.003）以及除典型的1p/19q共缺失外无其他DNA拷贝数变异（CNV）显著相关（p<0.001）。表观遗传学分析表明，TERTp野生型肿瘤在TERTp突变的少突胶质细胞瘤的最外围形成了一个独特的亚组。TERTp上游和近端区域的甲基化分析显示，与无基因改变一致，表观遗传调控在TERTp野生型少突胶质细胞瘤中不支持TERT过表达。WES显示TERTp野生型病例中无TM相关基因改变。Cox回归分析证实TERTp野生型状态是无进展生存期（PFS）更有利的独立预后因素（p=0.009）。