title: Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution.
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.
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors: Hoon
authors: H
authors: Kim
authors: 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;
authors: Siyuan
authors: S
authors: Zheng
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors: Seyed S
authors: SS
authors: Amini
authors: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;
authors: Selene M
authors: SM
authors: Virk
authors: Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA;
authors: Tom
authors: T
authors: Mikkelsen
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
authors: Daniel J
authors: DJ
authors: Brat
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors: Jonna
authors: J
authors: Grimsby
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors: Carrie
authors: C
authors: Sougnez
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors: Florian
authors: F
authors: Muller
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors: Jian
authors: J
authors: Hu
authors: 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;
authors: Andrew E
authors: AE
authors: Sloan
authors: 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;
authors: Mark L
authors: ML
authors: Cohen
authors: Department of Neurosurgery and Hematology and Medical Oncology, Winship Cancer Institute and School of Medicine, Emory University, Atlanta, Georgia 30322, USA;
authors: Erwin G
authors: EG
authors: Van Meir
authors: Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA;
authors: Lisa
authors: L
authors: Scarpace
authors: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;
authors: Peter W
authors: PW
authors: Laird
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors: John N
authors: JN
authors: Weinstein
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors: Eric S
authors: ES
authors: Lander
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors: Stacey
authors: S
authors: Gabriel
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
authors: Gad
authors: G
authors: Getz
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Matthew
authors: M
authors: Meyerson
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors: Lynda
authors: L
authors: Chin
authors: Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;
authors: Jill S
authors: JS
authors: Barnholtz-Sloan
authors: 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.
authors: Roel G W
authors: RG
authors: Verhaak
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D060965:Clonal Evolution / Q000235:genetics; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D059472:Exome; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53
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