Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Acta Neuropathol. 2015 May;129(5):669-78. doi: 10.1007/s00401-015-1405-4. Epub 2015 Mar 10.
Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease.
小儿脑胶质瘤(pedGBM)是儿童中最常见的恶性脑肿瘤之一,预后极差。与成人 GBM 不同,针对小儿脑胶质瘤的分子预后标志物很少。因此,我们通过对 202 例具有全面临床注释的小儿脑胶质瘤(1-18 岁)进行分子分析,研究了基因组和表观遗传改变的预后意义。通过直接测序或 FISH 筛选已知候选基因,对常规制备的福尔马林固定石蜡包埋肿瘤样本进行全基因组 DNA 甲基化谱分析。出乎意料的是,一部分组织学诊断为 GBM(n = 40,20%)的肿瘤表现出与低级别胶质瘤或多形性黄色星形细胞瘤(PXA)相似的甲基化谱。这些肿瘤的预后明显更好,分子上类似于 PXA 的肿瘤常携带 BRAF V600E 突变和 9p21(CDKN2A)纯合缺失。其余 162 例具有小儿脑胶质瘤分子特征的肿瘤包括四个亚组:H3.3 G34 突变(15%)、H3.3/H3.1 K27 突变(43%)、IDH1 突变(6%)和 H3/IDH 野生型(wt)GBM(36%)。这些亚组与特定的细胞遗传学异常、MGMT 甲基化模式和临床结果相关。对随访数据的分析确定了一组可用于风险分层的生物标志物:具有任何癌基因扩增和/或 K27M 突变的小儿脑胶质瘤(n = 124)是一个特别不利的群体,3 年总生存率(OS)为 5%,而没有这些标志物的肿瘤(n = 38)则定义了一个更有利的群体(3 年 OS~70%)。结合低级别样病变,近 40%的小儿脑胶质瘤病例具有与更好预后相关的独特分子特征。这种使用分子风险算法对小儿脑胶质瘤进行的精细预后方法,可能为这种破坏性疾病的治疗选择提供改善,并更好地规划临床试验分层。