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

被引：690

作者：

Venteicher, Andrew S. ^{[1
,2
,3
,4
,5
]}

Tirosh, Itay ^{[4
]}

Hebert, Christine ^{[1
,2
,3
,4
]}

Yizhak, Keren ^{[1
,2
,3
,4
]}

Neftel, Cyril ^{[1
,2
,3
,4
,6
]}

Filbin, Mariella G. ^{[1
,2
,3
,4
,7
,8
]}

Hovestadt, Volker ^{[1
,2
,3
,4
]}

Escalante, Leah E. ^{[1
,2
,3
,4
]}

Shaw, McKenzie L. ^{[1
,2
,3
,4
]}

Rodman, Christopher ^{[4
]}

Gillespie, Shawn M. ^{[1
,2
,3
]}

Dionne, Danielle ^{[4
]}

Luo, Christina C. ^{[1
,2
,3
]}

Ravichandran, Hiranmayi ^{[1
,2
,3
]}

Mylvaganam, Ravindra ^{[1
,2
,3
]}

Mount, Christopher ^{[9
,10
,11
,12
]}

Onozato, Maristela L. ^{[1
,2
,3
]}

Nahed, Brian V. ^{[3
,5
]}

Wakimoto, Hiroaki ^{[3
,5
]}

Curry, William T. ^{[3
,5
]}

Iafrate, A. John ^{[1
,2
,3
]}

Rivera, Miguel N. ^{[1
,2
,3
,4
]}

Frosch, Matthew P. ^{[1
,2
,3
]}

Golub, Todd R. ^{[4
,7
,8
,13
]}

Brastianos, Priscilla K. ^{[3
,14
,15
]}

Getz, Gad ^{[1
,2
,3
,4
]}

Patel, Anoop P. ^{[3
,5
]}

Monje, Michelle ^{[9
,10
,11
,12
]}

Cahill, Daniel P. ^{[3
,5
]}

Rozenblatt-Rosen, Orit ^{[4
]}

Louis, David N. ^{[1
,2
,3
]}

Bernstein, Bradley E. ^{[1
,2
,3
,4
]}

Regev, Aviv ^{[4
,13
,16
,17
]}

Suva, Mario L. ^{[1
,2
,3
,4
]}

机构：

[1] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[3] Harvard Med Sch, Boston, MA 02114 USA

[4] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[6] CHU Vaudois, Fac Biol & Med, Inst Pathol, CH-1011 Lausanne, Switzerland

[7] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

[8] Childrens Hosp, Ctr Canc, Boston, MA 02215 USA

[9] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA

[10] Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA

[11] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

[12] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[13] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[14] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[15] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[16] MIT, Koch Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[17] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

SCIENCE | 2017年 / 355卷 / 6332期

关键词：

REVEALS; HETEROGENEITY; LANDSCAPES; GENOMES; TISSUE; GENES; P53;

D O I：

10.1126/science.aai8478

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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