Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy.
Anatomic Pathology Unit, AUSL of Bologna, Via Altura 3, 40139, Bologna, Italy.
J Neurooncol. 2017 Nov;135(2):245-254. doi: 10.1007/s11060-017-2571-0. Epub 2017 Jul 26.
According to the 2016 World Health Organization (WHO) classification of tumors of the central nervous system, assessment of exon 4 mutations in isocitrate dehydrogenase 1 or 2 genes (IDH1 or IDH2) is an essential step in the characterization of gliomas. The p.R132H mutation is the most frequent alteration in IDH genes, however other non-canonical IDH mutations can be identified. The aim of this study is to investigate in depth the prevalence of non-R132H IDH ("non-canonical") mutations in brain tumors classified according to the 2016 WHO scheme and their clonal distribution in neoplastic cells. A total of 288 consecutive cases of brain gliomas (grade II-IV) were analyzed for exon 4 IDH1 and IDH2 mutations. IDH1 and IDH2 analysis was performed using next generation sequencing. Non-canonical IDH mutations were identified in 13/52 (25.0%) grade II gliomas (astrocytomas: 8/31, 25.8%; oligodendrogliomas: 5/21, 23.8%) and in 5/40 (12.5%) grade III gliomas (astrocytomas: 3/25, 12.0%; oligodendrogliomas: 2/15, 13.3%). They were not identified in 196 grade IV gliomas (192 glioblastomas, 4 gliosarcomas). In the large majority (>80%) of tumors IDH mutations, both IDH1-R132H and the non-canonical ones, were present in the large majority (>80%) of neoplastic cells. Our data highlight the importance of investigating not only the IDH1-R132H mutation but also the non-canonical ones. These mutations are clonally distributed, with proportions of mutated neoplastic cells overlapping with those of p.R132H, a finding consistent with their driver role in gliomagenesis.
根据 2016 年世界卫生组织（WHO）中枢神经系统肿瘤分类，对异柠檬酸脱氢酶 1 或 2 基因（IDH1 或 IDH2）外显子 4 突变的评估是胶质瘤特征的重要步骤。p.R132H 突变是 IDH 基因中最常见的改变，但也可以识别其他非典型 IDH 突变。本研究的目的是深入研究根据 2016 年 WHO 方案分类的脑肿瘤中非 R132H IDH（“非典型”）突变的流行率及其在肿瘤细胞中的克隆分布。对 288 例连续脑胶质瘤（II-IV 级）进行 IDH1 和 IDH2 外显子 4 突变分析。使用下一代测序进行 IDH1 和 IDH2 分析。在 52 例 II 级胶质瘤（星形细胞瘤：31 例，25.8%；少突胶质细胞瘤：21 例，23.8%）和 40 例 III 级胶质瘤（星形细胞瘤：25 例，12.0%；少突胶质细胞瘤：15 例，13.3%）中发现了 13 例非典型 IDH 突变。在 196 例 IV 级胶质瘤（192 例胶质母细胞瘤，4 例胶质肉瘤）中未发现。在大多数肿瘤（>80%）中，IDH 突变，包括 IDH1-R132H 和非典型突变，存在于大多数（>80%）肿瘤细胞中。我们的数据强调了不仅要调查 IDH1-R132H 突变，还要调查非典型突变的重要性。这些突变是克隆分布的，突变肿瘤细胞的比例与 p.R132H 重叠，这一发现与其在胶质瘤发生中的驱动作用一致。
