title: Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq.
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.
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrew S
authors.identifier: 0000-0003-0643-0493
authors.initials: AS
authors.lastname: Venteicher
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. suva.mario@mgh.harvard.edu aregev@broadinstitute.org tirosh@broadinstitute.org.
authors.forename: Itay
authors.identifier: 0000-0001-5477-2987
authors.initials: I
authors.lastname: Tirosh
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hebert
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Yizhak
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: Cyril
authors.identifier: 0000-0002-6356-1142
authors.initials: C
authors.lastname: Neftel
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA.
authors.forename: Mariella G
authors.initials: MG
authors.lastname: Filbin
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Escalante
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: McKenzie L
authors.initials: ML
authors.lastname: Shaw
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rodman
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Shawn M
authors.identifier: 0000-0003-1913-0860
authors.initials: SM
authors.lastname: Gillespie
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Dionne
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Christina C
authors.identifier: 0000-0001-9872-7432
authors.initials: CC
authors.lastname: Luo
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hiranmayi
authors.initials: H
authors.lastname: Ravichandran
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ravindra
authors.identifier: 0000-0001-5336-6557
authors.initials: R
authors.lastname: Mylvaganam
authors.affiliation: Departments of Neurology, Neurosurgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mount
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Maristela L
authors.initials: ML
authors.lastname: Onozato
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Nahed
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Todd R
authors.identifier: 0000-0003-0113-2403
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Departments of Medicine and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Gad
authors.identifier: 0000-0002-0936-0753
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Anoop P
authors.identifier: 0000-0001-7078-9535
authors.initials: AP
authors.lastname: Patel
authors.affiliation: Departments of Neurology, Neurosurgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Monje
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Daniel P
authors.identifier: 0000-0003-2552-6546
authors.initials: DP
authors.lastname: Cahill
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Rozenblatt-Rosen
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David N
authors.identifier: 0000-0002-9423-4099
authors.initials: DN
authors.lastname: Louis
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Bradley E
authors.identifier: 0000-0002-5726-6278
authors.initials: BE
authors.lastname: Bernstein
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. suva.mario@mgh.harvard.edu aregev@broadinstitute.org tirosh@broadinstitute.org.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.|Koch Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Aviv
authors.identifier: 0000-0003-3293-3158
authors.initials: A
authors.lastname: Regev
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. suva.mario@mgh.harvard.edu aregev@broadinstitute.org tirosh@broadinstitute.org.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Mario L
authors.identifier: 0000-0001-9898-5351
authors.initials: ML
authors.lastname: Suvà
mesh_terms: D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D019070:Cell Lineage; D005910:Glioma / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008264:Macrophages; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D025341:Principal Component Analysis; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D059016:Tumor Microenvironment
chemical_list: D007521:Isocitrate Dehydrogenase