Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Mod Pathol. 2021 Jul;34(7):1236-1244. doi: 10.1038/s41379-021-00795-w. Epub 2021 Mar 26.
The 2016 WHO classifies IDH-mutant gliomas into oligodendroglioma or diffuse astrocytoma based on co-occurring genetic events. Recent literature addresses the concept of stratifying IDH-mutant gliomas based on prognostically significant molecular events. However, the presence of a second class-defining driver alteration in IDH-mutant gliomas has not been systematically described. We searched the sequencing database at our institutions as well as The Cancer Genome Atlas (TCGA) and cBioPortal for IDH-mutant gliomas with other potentially significant alterations. For each case, we reviewed the clinical information, histology and genetic profile. Of 1702 gliomas tested on our targeted exome sequencing panel, we identified 364 IDH-mutated gliomas, four of which had pathogenic FGFR alterations and one with BRAF V600E mutation. Five additional IDH-mutant gliomas with NTRK fusions were identified through collaboration with an outside institution. Also, a search in the glioma database in cBioPortal (5379 total glioma samples, 1515 cases [28.1%] with IDH1/2 mutation) revealed eight IDH-mutated gliomas with FGFR, NTRK or BRAF pathogenic alterations. All IDH-mutant gliomas with dual mutations identified were hemispheric and had a mean age at diagnosis of 36.2 years (range 16-55 years old). Co-occurring genetic events involved MYCN, RB and PTEN. Notable outcomes included a patient with an IDH1/FGFR1-mutated anaplastic oligodendroglioma who has survived 20 years after diagnosis. We describe a series of 18 IDH-mutant gliomas with co-occurring genetic events that have been described as independent class-defining drivers in other gliomas. While these tumors are rare and the significance of these alterations needs further exploration, alterations in FGFR, NTRK, and BRAF could have potential therapeutic implications and affect clinical trial design and results in IDH-mutant studies. Our data highlights that single gene testing for IDH1 in diffuse gliomas may be insufficient for detection of targets with potential important prognostic and treatment value.
2016 年世界卫生组织根据同时存在的遗传事件，将 IDH 突变型神经胶质瘤分为少突胶质细胞瘤或弥漫性星形细胞瘤。最近的文献探讨了根据具有预后意义的分子事件对 IDH 突变型神经胶质瘤进行分层的概念。然而，在 IDH 突变型神经胶质瘤中存在第二个明确的驱动改变尚未得到系统描述。我们在我们的机构以及癌症基因组图谱 (TCGA) 和 cBioPortal 的测序数据库中搜索了具有其他潜在重要改变的 IDH 突变型神经胶质瘤。对于每个病例，我们回顾了临床信息、组织学和遗传特征。在我们的靶向外显子组测序面板上测试的 1702 例神经胶质瘤中，我们鉴定出 364 例 IDH 突变型神经胶质瘤，其中 4 例存在致病性 FGFR 改变，1 例存在 BRAF V600E 突变。通过与外部机构合作，还鉴定出 5 例具有 NTRK 融合的 IDH 突变型神经胶质瘤。此外，在 cBioPortal 的神经胶质瘤数据库中进行搜索（总共有 5379 例神经胶质瘤样本，其中 1515 例 [28.1%] 存在 IDH1/2 突变）显示 8 例 IDH 突变型神经胶质瘤存在 FGFR、NTRK 或 BRAF 致病性改变。鉴定出的所有具有双重突变的 IDH 突变型神经胶质瘤均为半球性，诊断时的平均年龄为 36.2 岁（16-55 岁）。同时存在的遗传事件涉及 MYCN、RB 和 PTEN。显著的结局包括一名 IDH1/FGFR1 突变的间变性少突胶质细胞瘤患者，诊断后已经存活了 20 年。我们描述了一系列 18 例 IDH 突变型神经胶质瘤，这些肿瘤同时存在遗传事件，这些遗传事件在其他神经胶质瘤中被描述为独立的明确的驱动因素。虽然这些肿瘤较为罕见，这些改变的意义需要进一步探讨，但 FGFR、NTRK 和 BRAF 的改变可能具有潜在的治疗意义，并影响 IDH 突变型研究的临床试验设计和结果。我们的数据强调，弥漫性神经胶质瘤中 IDH1 的单一基因检测可能不足以检测具有潜在重要预后和治疗价值的靶点。
