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Cancer Cell. 2017 Jul 10;32(1):42-56.e6. doi: 10.1016/j.ccell.2017.06.003.

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.

Author information

1
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Texas-Houston Graduate School in Biomedical Sciences, Houston, TX 77030, USA.
4
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
5
Cancer Cell Biology Programme, Seve Ballesteros Foundation Brain Tumor Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain.
6
Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
7
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China; Collaborative Innovation Center for Cardiovascular Disease, Nanjing Medical University, Nanjing 211166, China.
8
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea.
9
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
11
Departments of Pathology and Laboratory Medicine, Neurosurgery Medical University of South Carolina, and Hollings Cancer Center, Charleston, SC 29425, USA.
12
Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milano, Italy.
13
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
14
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
15
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
16
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
17
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: epsulman@mdanderson.org.
18
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea; Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea. Electronic address: nsnam@skku.edu.
19
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. Electronic address: roel.verhaak@jax.org.

Abstract

We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.

KEYWORDS:

disease recurrence; glioblastoma; immune cells; macrophages/microglia; mesenchymal subtype; proneural to mesenchymal transition; tumor evolution; tumor microenvironment

PMID:
28697342
PMCID:
PMC5599156
DOI:
10.1016/j.ccell.2017.06.003
[Indexed for MEDLINE]
Free PMC Article

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