Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial
Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial
复制标题
DOI：
10.1093/neuonc/nov182
复制
发表时间：
2016-03-01
期刊：
影响因子：
15.9
通讯作者：
van den Bent, Martin J.
中科院分区：
文献类型：
--
作者：
Dubbink, Hendrikus J.;Atmodimedjo, Peggy N.;van den Bent, Martin J.
弥漫性胶质瘤的组织学诊断受观察者间差异的影响，并与主要预后和预测分子异常适度相关。我们研究了一系列在EORTC III期试验26951中纳入的局部诊断为间变性少突胶质细胞瘤的患者，这些患者接受了丙卡巴肼/洛莫司汀/长春新碱（PCV）化疗，以探讨其诊断、预后、和下一代靶向测序（NGS）在弥漫性胶质瘤中的预测价值，并评估FUBP 1和CIC突变的预后影响。用靶向NGS检测包埋样品中ATRX、TP 53、IDH 1、IDH 2、CIC、FUBP 1、PI 3 KC、TERT、EGFR、H3 F3 A、BRAF、PTEN和NOTCH的突变以及染色体1 p、19 q、10 q和7的拷贝数改变。我们还用PCR技术对139例患者进行了端粒酶逆转录酶突变的检测，其中6例的检测结果不能提供信息。126例肿瘤可分类为：20例为II型（IDH突变[mut]，“星形细胞瘤”），49例为I型（1 p/19 q共缺失，“少突胶质细胞瘤”），55例为III型（7+/10 q-或TERTmut和1 p/19 q完整，“胶质母细胞瘤”），2例为儿童胶质母细胞瘤（H3 F3 Amut），其余7例未分类（共91%分类）。分子分型具有明确的预后意义，与预后的相关性优于经典的组织病理学。在1 p/19 q共缺失肿瘤中，CIC和FUBP 1突变不影响预后。MGMT启动子甲基化仍然是PCV化疗生存获益的最具预测性因素。靶向NGS可将弥漫性胶质瘤临床相关分类为具有非常不同结局的组。弥漫性胶质瘤的诊断应以分子分型为基础，并结合组织病理学分级，进一步探讨弥漫性胶质瘤分子分型的最低要求。
Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact of FUBP1 and CIC mutations.Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR.Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], "astrocytoma"), 49 as type I (1p/19q codeletion, "oligodendroglioma"), 55 as type III (7+/10q- or TERTmut and 1p/19q intact, "glioblastoma"), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy.Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.