Format

Send to

Choose Destination
Genome Res. 2015 Mar;25(3):316-27. doi: 10.1101/gr.180612.114. Epub 2015 Feb 3.

Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution.

Author information

1
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
2
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
3
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;
4
Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA;
5
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
6
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
7
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
8
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA; Brain Tumor and Neuro-oncology Center, Department of Neurosurgery, University Hospitals Case Medical Center, Case Western Reserve School of Medicine, Cleveland, Ohio 44106, USA;
9
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA;
10
Department of Neurosurgery and Hematology and Medical Oncology, Winship Cancer Institute and School of Medicine, Emory University, Atlanta, Georgia 30322, USA;
11
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
12
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
13
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; rverhaak@mdanderson.org.

Abstract

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ∼ 7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity.

PMID:
25650244
PMCID:
PMC4352879
DOI:
10.1101/gr.180612.114
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substance, Grant support

Publication types

MeSH terms

Substance

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center