Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq.

Journal: 
Science
Publication Year: 
2017
Authors: 
Andrew S Venteicher
Itay Tirosh
Christine Hebert
Keren Yizhak
Cyril Neftel
Mariella G Filbin
Volker Hovestadt
Leah E Escalante
McKenzie L Shaw
Christopher Rodman
Shawn M Gillespie
Danielle Dionne
Christina C Luo
Hiranmayi Ravichandran
Ravindra Mylvaganam
Christopher Mount
Maristela L Onozato
Brian V Nahed
Hiroaki Wakimoto
William T Curry
A John Iafrate
Miguel N Rivera
Matthew P Frosch
Todd R Golub
Priscilla K Brastianos
Gad Getz
Anoop P Patel
Michelle Monje
Daniel P Cahill
Orit Rozenblatt-Rosen
David N Louis
Bradley E Bernstein
Aviv Regev
Mario L Suva
PubMed link: 
28360267
Public Summary: 
Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
Scientific Abstract: 
Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.