Immunological profiles of human oligodendrogliomas define two distinct molecular subtypesResearch in context
Fan Wu,
Yi-Yun Yin,
Wen-Hua Fan,
You Zhai,
Ming-Chen Yu,
Di Wang,
Chang-Qing Pan,
Zheng Zhao,
Guan-Zhang Li,
Wei Zhang
Affiliations
Fan Wu
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China; Corresponding author. Nan Si Huan Xi Lu 119, Fengtai District, Beijing 100070, China.
Yi-Yun Yin
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Wen-Hua Fan
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
You Zhai
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Ming-Chen Yu
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Di Wang
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Chang-Qing Pan
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Zheng Zhao
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Guan-Zhang Li
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China
Wei Zhang
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, 100070, China; Corresponding author. Nan Si Huan Xi Lu 119, Fengtai District, Beijing 100070, China.
Summary: Background: Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome. Methods: 137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation. Findings: We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts. Interpretation: This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas. Funding: The funders are listed in the Acknowledgement.
