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Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):19098-19108. doi: 10.1073/pnas.1813495116. Epub 2019 Aug 30.

Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments.

Author information

1
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4S6.
2
Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
3
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6H 3N1.
4
Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 1N4.
5
Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N2.
6
Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 2T9.
7
Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada T2N 4Z6.
8
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
9
Clark H. Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada T2N 4Z6.
10
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada T2N 4N1.
11
Department of Cell Biology & Anatomy, University of Calgary, Calgary, AB, Canada T2N 4N1.
12
Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1.
13
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB, Canada T2L 2K8.
14
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8.
15
Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada T2N 2T9.
16
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4S6; sjones@bcgsc.ca.

Abstract

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of MGMT expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.

KEYWORDS:

BTICs; genome; glioblastoma; therapy; transcriptome

PMID:
31471491
DOI:
10.1073/pnas.1813495116

Conflict of interest statement

The authors declare no conflict of interest.

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