Acquired genetic and cell-state changes in IDH-mutant glioma progression
Abstract
Abstract Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment 1,2 . However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial–neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma 3,4 . Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
Article Details
Authors (51)
Kevin C. Johnson
Avishay Spitzer
Frederick S. Varn
Masashi Nomura
Luciano Garofano
Tamrin Chowdhury
Anuja Lipsa
Linbin Zhang
Ester Calvo Fernández
Tanyeri Barak
A. Gulhan Ercan-Sencicek
Ayse Buket Peksen
Kevin J. Anderson
C. Mircea S. Tesileanu
Samirkumar B. Amin
Emre Kocakavuk
Dacheng Zhao
Fulvio D’Angelo
Simona Migliozzi
Lillian Bussema
Simon Gritsch
Hyo-Eun Moon
Sun Ha Paek
Franck Bielle
Alice Laurenge
Anna Luisa Di Stefano
Bertrand Mathon
Alberto Picca
Marc Sanson
Ann-Christin Hau
Frank Hertel
Kamil Grzyb
Zheng Zhao
Qianghu Wang
Tao Jiang
Julie J. Miller
Hiroaki Wakimoto
Daniel P. Cahill
Massachusetts General Hospital Cancer Center Boston Massachusetts USA
Jennifer Moliterno
Murat Gunel
Beth Hermes
Nader Sanai
Anna Golebiewska
Simone P. Niclou
Jason Huse
W. K. Alfred Yung
Anna Lasorella
Mario L. Suvà
Antonio Iavarone
Itay Tirosh
Roel G. W. Verhaak