Paul Yashna, Mondal Baisakhi, Patil Vikas, Somasundaram Kumaravel
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012 India.
Clin Epigenetics. 2017 Apr 4;9:32. doi: 10.1186/s13148-017-0331-9. eCollection 2017.
Glioma is the most common of all primary brain tumors with poor prognosis and high mortality. The 2016 World Health Organization classification of the tumors of central nervous system uses molecular parameters in addition to histology to redefine many tumor entities. The new classification scheme divides diffuse gliomas into low-grade glioma (LGG) and glioblastoma (GBM) as per histology. LGGs are further divided into isocitrate dehydrogenase (IDH) wild type or mutant, which is further classified into either oligodendroglioma that harbors 1p/19q codeletion or diffuse astrocytoma that has an intact 1p/19q loci but enriched for ATRX loss and TP53 mutation. GBMs are divided into IDH wild type that corresponds to primary or de novo GBMs and IDH mutant that corresponds to secondary or progressive GBMs. To make the 2016 WHO subtypes of diffuse gliomas more robust, we carried out Prediction Analysis of Microarrays (PAM) to develop DNA methylation signatures for these subtypes.
In this study, we applied PAM on a training set of diffuse gliomas derived from The Cancer Genome Atlas (TCGA) and identified DNA methylation signatures to classify LGG IDH wild type from LGG IDH mutant, LGG IDH mutant with 1p/19q codeletion from LGG IDH mutant with intact 1p/19q loci and GBM IDH wild type from GBM IDH mutant with an accuracy of 99-100%. The signatures were validated using the test set of diffuse glioma samples derived from TCGA with an accuracy of 96 to 99%. In addition, we also carried out additional validation of all three signatures using independent LGG and GBM cohorts. Further, the methylation signatures identified a fraction of samples as discordant, which were found to have molecular and clinical features typical of the subtype as identified by methylation signatures.
Thus, we identified methylation signatures that classified different subtypes of diffuse glioma accurately and propose that these signatures could complement 2016 WHO classification scheme of diffuse glioma.
胶质瘤是所有原发性脑肿瘤中最常见的，预后差且死亡率高。2016年世界卫生组织中枢神经系统肿瘤分类除了组织学外还使用分子参数来重新定义许多肿瘤实体。新的分类方案根据组织学将弥漫性胶质瘤分为低级别胶质瘤（LGG）和胶质母细胞瘤（GBM）。LGG进一步分为异柠檬酸脱氢酶（IDH）野生型或突变型，其中IDH突变型又进一步分为携带1p/19q共缺失的少突胶质细胞瘤或1p/19q位点完整但富含ATRX缺失和TP53突变的弥漫性星形细胞瘤。GBM分为对应于原发性或新发GBM的IDH野生型和对应于继发性或进展性GBM的IDH突变型。为了使2016年WHO弥漫性胶质瘤亚型分类更可靠，我们进行了微阵列预测分析（PAM）以开发这些亚型的DNA甲基化特征。
在本研究中，我们将PAM应用于来自癌症基因组图谱（TCGA）的弥漫性胶质瘤训练集，并鉴定了DNA甲基化特征以区分LGG IDH野生型与LGG IDH突变型、携带1p/19q共缺失的LGG IDH突变型与1p/19q位点完整的LGG IDH突变型以及GBM IDH野生型与GBM IDH突变型，准确率为99%-100%。使用来自TCGA的弥漫性胶质瘤样本测试集对这些特征进行验证，准确率为96%至99%。此外，我们还使用独立的LGG和GBM队列对所有三个特征进行了额外验证。此外，甲基化特征将一部分样本鉴定为不一致，这些样本被发现具有甲基化特征所确定的该亚型典型的分子和临床特征。
因此，我们鉴定出了能够准确区分弥漫性胶质瘤不同亚型的甲基化特征，并提出这些特征可补充2016年WHO弥漫性胶质瘤分类方案。
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