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

Andrew S. Venteicher(Broad Institute), Itay Tirosh(Broad Institute), Christine Hebert(Broad Institute), Keren Yizhak(Broad Institute), Cyril Neftel(Broad Institute), Mariella G. Filbin(Broad Institute), Volker Hovestadt(Broad Institute), Leah E. Escalante(Broad Institute), McKenzie Shaw(Broad Institute), Christopher Rodman(Broad Institute), Shawn Gillespie(Harvard University), Danielle Dionne(Broad Institute), Christina C. Luo(Harvard University), Hiranmayi Ravichandran(Harvard University), Ravindra Mylvaganam(Harvard University), Christopher Mount(Stanford Medicine), Maristela L. Onozato(Harvard University), Brian V. Nahed(Harvard University), Hiroaki Wakimoto(Harvard University), William T. Curry(Harvard University), A. John Iafrate(Harvard University), Miguel N. Rivera(Broad Institute), Matthew P. Frosch(Harvard University), Todd R. Golub(Broad Institute), Priscilla K. Brastianos(Massachusetts General Hospital), Gad Getz(Broad Institute), Anoop P. Patel(Harvard University), Michelle Monje(Stanford Medicine), Daniel P. Cahill(Harvard University), Orit Rozenblatt–Rosen(Broad Institute), David N. Louis(Harvard University), B Bernstein(Broad Institute), Aviv Regev(Broad Institute), Mario L. Suvà(Broad Institute)
Science
March 30, 2017
10.1126/science.aai8478
Cited by 1,054Open Access
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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.

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