EPCO-26. LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA

Abstract Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood. To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing. Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles. Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.

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Journal
Neuro-Oncology
Published
2024-11-01
DOI
https://doi.org/10.1093/neuonc/noae165.0025
Citations
1
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.44
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article

EPCO-26. LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA

Qianghu Wang, Itay Tirosh, W.K. Alfred Yung, Anuja Lipsa et al.
1 citations
Neuro-Oncology
Glioma Diagnosis and Treatment
0.44
article

EPCO-26. LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA

Qianghu Wang, Itay Tirosh, W.K. Alfred Yung, Anuja Lipsa, Mario L. Suvà, Luciano Garofano, Masashi Nomura, Frederick S. Varn, Jason T. Huse, Fulvio D’Angelo, Bertrand Mathon, Hyo-Eun Moon, Alice Laurenge, Avishay Spitzer, Nader Sanai, Anna Golebiewska, Kevin J. Anderson, Franck Bielle, Roel G.W. Verhaak, Beth Hermes, Simone P. Niclou, Anna Lasorella, Sun Ha Paek, Kevin C. Johnson, Young Taek Oh, Simon Gritsch, Marc Sanson, Tao Jiang, Tamrin Chowdhury, Lillian Bussema, Antonio Iavarone, Anna Luisa Di Stefano, Alberto Pïcca, Zheng Zhao, Frank Hertel
article en
1 citations

Abstract

Abstract Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood. To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing. Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles. Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.

Neuro-OncologyVol. 26(Supplement_8)
Broad Institute (US), Barrow Neurological Institute (US), St. Joseph's Hospital and Medical Center (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Seoul National University (KR), University of Miami (US), Capital Medical University (CN), Tel Aviv Sourasky Medical Center (IL), Yale University (US), Sorbonne Université (FR), Massachusetts General Hospital (US), Assistance Publique – Hôpitaux de Paris (FR), Luxembourg Institute of Health (LU), Beijing Institute of Neurosurgery (CN), Jackson Laboratory (US), Advanced Institute of Convergence Technology (KR), Pitié-Salpêtrière Hospital (FR), Jiangsu Cancer Hospital (CN), Ospedale di Livorno (IT), Center for Cancer Research (US), Hôpital Foch (FR), Sylvester Comprehensive Cancer Center (US), Neurological Surgery (US), Weizmann Institute of Science (IL), UConn Health (US), Nanjing Medical University (CN)
Good health and well-being
Openalex Percentile: Top 31%
Glioma Diagnosis and Treatment
0.44
DOIOpen Access PDFOpenAlex
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