Molecular subtyping reveals immune alterations in IDH wild-type lower-grade diffuse glioma.

Wu, Fan; Li, Guan-Zhang; Liu, Han-Jie; Zhao, Zheng; Chai, Rui-Chao; Liu, Yu-Qing; Jiang, Hao-Yu; Zhai, You; Feng, Yue-Mei; Li, Ren-Peng; Zhang, Wei

Isocitrate dehydrogenase (IDH) wild-type diffuse lower-grade glioma (LGG) is usually associated with poor outcome, but there have been disputes over its clinical outcome and classification. We presented here a robust gene expression-based molecular classification of IDH wild-type diffuse LGG into two subtypes with distinct biological and clinical features. A discovery cohort of 49 IDH wild-type diffuse LGGs from Chinese Glioma Genome Atlas (CGGA) was subjected to clustering and function analysis. 73 tumors from The Cancer Genome Atlas (TCGA) were used to validate our findings. Consensus clustering of transcriptional data uncovered concordant classification of two robust and prognostically significant subtypes of IDH wild-type LGG. Sub1, associated with poorer outcomes, was characterized by significantly higher immune, cytolytic scores, M2 macrophages and up-regulation of immune exhaustion markers; while Sub2 who had elevated lymphocytes and plasma cells showed relatively favorable survival. Somatic alteration analysis revealed Sub1 showed more frequently deleted regions, such as locus of CDKN2A/CDKN2B, DMRTA1, C9orf53 and MTAP. Furthermore, we developed and validated a five-gene signature for better application of this acquired stratification. Our data demonstrate the biological and prognostic heterogeneity within IDH wild-type diffuse LGGs and deepen our molecular understanding of this tumor entity. This article is protected by copyright. All rights reserved.