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Frontiers of Medicine

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Front. Med.    2023, Vol. 17 Issue (2) : 240-262    https://doi.org/10.1007/s11684-022-0936-z
RESEARCH ARTICLE
Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma
Jing Feng1, Zheng Zhao2, Yanfei Wei1, Zhaoshi Bao3, Wei Zhang3, Fan Wu2, Guanzhang Li2, Zhiyan Sun2, Yanli Tan4, Jiuyi Li5, Yunqiu Zhang6, Zejun Duan7, Xueling Qi7, Kai Yu8, Zhengmin Cong1, Junjie Yang1, Yaxin Wang1, Yingyu Sun1, Fuchou Tang8, Xiaodong Su8, Chuan Fang9(), Tao Jiang2,3,10(), Xiaolong Fan1,10()
1. Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing 100875, China
2. Beijing Neurosurgical Institute, Beijing 100070, China
3. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
4. Department of Pathology, Affiliated Hospital of Hebei University, Baoding 071000, China
5. Gendya Biotechnology Ltd., Beijing 100176, China
6. Center of Growth Metabolism & Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
7. Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China
8. Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China
9. Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 071000, China; Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma, Baoding 071000, China
10. Chinese Glioma Genome Atlas Network (CGGA), Beijing 100070, China
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Abstract

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.
Keywords glioma progression      molecular classification      EM/PM subtyping      intratumor heterogeneity     
Corresponding Author(s): Chuan Fang,Tao Jiang,Xiaolong Fan   
Just Accepted Date: 20 October 2022   Online First Date: 10 January 2023    Issue Date: 26 May 2023
 Cite this article:   
Jing Feng,Zheng Zhao,Yanfei Wei, et al. Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma[J]. Front. Med., 2023, 17(2): 240-262.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0936-z
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I2/240
Fig.1  EM/PM subtype-specific clinical and genomic features. (A and B) Left: heatmap of the NT identifier and the EM and PM modules in the transcriptome of 325 CGGA or 701 TCGA adult gliomas; the results of histological diagnosis are also shown. Right: Kaplan–Meier plots of OS, median OS, and age at diagnosis for the EM and PM subtypes. The OS data were analyzed using log-rank tests and the age at diagnosis by using Mann–Whitney-U test. A, astrocytoma grades II–III; O, oligodendroglioma grades II–III; OA, oligoastrocytoma grade III. (C) Landscape of the canonical genomic alterations derived from the TCGA samples. (D) Poorer OS of PM gliomas without 1p19q co-deletion compared with PM gliomas with 1p19q co-deletion.
Fig.2  Temporal stability of the EM/PM molecular subtypes. (A) Unsupervised consensus clustering in 141 transcriptomes of 70 paired longitudinal gliomas from CGGA for the signatures of EM/PM modules and NT identifier. CDF plot (left) and consensus matrix for k = 3 (right) are shown. (B) Heatmap of the EM, PM, and NT signatures across the 141 longitudinal samples. (C) Maintenance of the EM/PM subtypes between the primary/recurrent pairs. (D) Kaplan–Meier plot and log-rank test for the PFS of the paired longitudinal gliomas according to their EM/PM subtypes. (E) Kaplan–Meier plot and log-rank test for the OS of the paired longitudinal gliomas according to their EM/PM subtypes. (F) Maintenance of high expression of EM marker ELOVL2 but weak expression of PM marker DLL3 in a representative pair of primary (Pri.) and recurrent (Rec.) EM glioma. (G) Maintenance of high expression of PM marker DLL3, but weak expression of EM marker ELOVL2 in a representative pair of primary and recurrent PM glioma.
Fig.3  Spatial stability of the EM/PM molecular subtypes. (A) Persistent EM/PM subtypes and canonical genomic alterations in multiregional samples of 12 GBMs from the CGGA. (B) Persistent EM/PM subtypes in multiregional samples of GBM samples from the Ivy Glioblastoma Atlas. (C) Temporal and spatial maintenance of the EM/PM subtypes in multiregional samples from five TCGA patients. EM/PM subtyping results for the samples from primary (P) and recurrent (R) surgeries are shown.
Fig.4  Non-overlapping expression of the EM and PM signatures at the single-cell level. (A) t-SNE plot of cell populations identified. (B) Malignant cells in the EM gliomas analyzed harbored gain of chromosome 7 and loss of chromosome 10, and malignant cells in the PM gliomas analyzed harbored 1p19q co-deletion. OLs, Mf/MGs, and T cells served as the control in CNV analysis. (C) Heatmap of the differential expression of SOX2, EM/PM signatures, and lineage markers of non-malignant cells across the cell populations. (D) Frequencies of cell populations in individual samples. OLs, Mf/MGs, and T cells were assigned into the TME fraction. (E) Reciprocal expression between the EM and PM members in the malignant cell populations in four representative gliomas are shown. EGFR and regulators of gliogenic switch (NFIA and SOX9) or OPC specification (PDGFRA, OLIG1, OLIG2, SOX4, SOX6, and SOX8) are highlighted.
Fig.5  Resemblance of glioma cell populations to distinct V-SVZ stem/progenitor cell compartment. (A and B) CCA results for correlation of transcriptomes of individual glioma cells to the single cell transcriptomes in the adult mouse V-SVZ. (C and D) Heatmaps depicting enriched expression of the signature genes in EM++ or EM+++ cell population in astrocytes and neurons at P = 0.0001. (E and F) Heatmaps depicting enriched expression of the signatures in EM+PM++ or PM+++ cell population in OPCs at P = 0.0001.
Fig.6  Activities of cell proliferation and microenvironment together predict glioma progression and aggressiveness. (A) Elevated macrophage and vascular endothelial cell fractions in EM gliomas and recurrent PM gliomas. (B) Heatmap of PR0.01 expression across the primary and recurrent glioma samples under the EM/PM classification scheme. Normalized mean expression levels of PR0.01 signature in the primary and recurrent EM or PM samples are shown. In comparison with primary PM gliomas, PR0.01 expression was significantly higher in the recurrent PM gliomas (P < 0.0001, t-test). (C) Depiction of the protein–protein association network among the PR0.01 members. In total, 86 PR0.01 members with a combined association score > 0.99 and degree > 6 in the STRING database were included to depict this network by using Cytoscape. The nodes are color-coded according to the functional categories in DAVID bioinformatics resources, and their sizes correspond to the extent of association. (D) Results of multivariate Cox regression analyses for the PR0.01 score controlled by age at diagnosis, 1p19q co-deletion, and MKI67 score in the IDH mutant/PM gliomas. (E) High expression of PR0.01 signature is correlated to poor prognosis. Patients were grouped into quartiles 1 to 4 of the PR0.01 expression. Kaplan–Meier plots and results of log-rank tests are shown.
Fig.7  Robust maintenance of the EM and PM molecular subtypes during glioma progression. The EM and PM gene co-expression modules are anchored in NSC compartment and oligodendrocyte precursor compartment, respectively. While the EM molecular subtype originates from the NSC compartment and harbors gain of chromosome 7 and loss of chromosome 10 as the canonical genomic alterations, the PM subtype originates from the oligodendrocyte precursors and harbors IDH mutation as the canonical genomic alteration. During glioma progression, the EM and PM subtypes are robustly maintained, although the primary and recurrent samples from the same patient can differ significantly in terms of the histological features and compositions of genomic alterations. Images of HE staining of paired primary and recurrent samples from representative EM or PM gliomas are shown.
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