Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Acta Neuropathol. 2014 Oct;128(4):561-71. doi: 10.1007/s00401-014-1315-x. Epub 2014 Jul 10.
The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP(pos) (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP(neg) (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP(neg) glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP(pos) tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP(pos) tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP(neg) anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.
间变性神经胶质瘤患者的预后差异很大。基于大规模基因组或表观基因组分析的间变性神经胶质瘤的分子分类是否优于组织病理学，以反映不同的生物学群体、预测预后和指导治疗决策，仍有待确定。在包括 115 名 NOA-04 试验患者在内的 228 名间变性神经胶质瘤（星形细胞瘤、少突星形细胞瘤和少突胶质细胞瘤）患者队列中，进行了基于平台的全基因组 DNA 甲基化分析，该平台还允许检测拷贝数异常。我们还将这些肿瘤与 55 例胶质母细胞瘤进行了比较。未受监督的 DNA 甲基化模式聚类显示与 IDH 状态相关的两个主要组：CpG 岛甲基化表型（CIMP）阳性（77.5%）或阴性（22.5%）。CIMP(pos)（IDH 突变）肿瘤根据 1p 和 19q 染色体臂的拷贝数状态进一步分离。CIMP(neg)（IDH 野生型）肿瘤显示出胶质母细胞瘤的标志性拷贝数改变，并与 CIMP(neg)胶质母细胞瘤聚集在一起，而不根据 WHO 分级形成单独的组。值得注意的是，没有分子证据表明存在代表间变性少突星形细胞瘤的独特生物学实体。基于 CIMP 和 1p/19q 状态的肿瘤分类与生存显著相关，允许比当前的组织病理学分类更好地预测结果：具有 1p/19q 缺失（CIMP-codel）的 CIMP(pos)肿瘤患者预后最好，其次是具有 CIMP(pos)肿瘤但 1p/19q 状态完整的患者（CIMP-non-codel）。具有 CIMP(neg)间变性神经胶质瘤（胶质母细胞瘤样）的患者预后最差。总的来说，我们的数据表明，间变性神经胶质瘤可以根据 IDH 和 1p/19q 状态分为三个分子组，这些组与潜在生物学有明显联系，并与前瞻性试验队列的临床结果有显著关联。
