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

• Type of Material: Article
• Authors: Hoon Kim, University of Texas MD Anderson Cancer Center; Siyuan Zheng, University of Texas MD Anderson Cancer Center; Seyed S. Amini, University of Texas MD Anderson Cancer Center; Selene M. Virk, Case Western Reserve University; Tom Mikkelsen, Henry Ford Hospital; Daniel Brat, Emory University; Jonna Grimsby, Broad Institute of MIT and Harvard; Carrie Sougnez, Broad Institute of MIT and Harvard; Florian Muller, University of Texas MD Anderson Cancer Center; Jian Hu, University of Texas MD Anderson Cancer Center; Andrew E. Sloan, Case Western Reserve University; Mark L. Cohen, Case Western Reserve University; Erwin Van Meir, Emory University; Lisa Scarpace, Henry Ford Hospital; Peter W. Laird, Van Andel Research Institute; John N. Weinstein, University of Texas MD Anderson Cancer Center; Eric S. Lander, Broad Institute of MIT and Harvard; Stacey Gabrie, Broad Institute of MIT and Harvard; Gad Getz, Broad Institute of MIT and Harvard; Matthew Meyerson, Broad Institute of MIT and Harvard; Lynda Chin, University of Texas MD Anderson Cancer Center; Jill S. Barnholtz-Sloan, Case Western Reserve University; Roel G.W. Verhaak, University of Texas MD Anderson Cancer Center
• Language: English
• Date: 2015-03-01
• Publisher: Cold Spring Harbor Laboratory Press
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Kim et al.; Published by Cold Spring Harbor Laboratory Press
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/gr.180612.114
• Title of Journal or Parent Work: Genome Research
• ISSN: 1088-9051
• Volume: 25
• Issue: 3
• Start Page: 316
• End Page: 327
• Grant/Funding Information: This work is supported by grants from the NCI, grant numbers P50 CA127001, P50 CA083639-12, P01 CA085878, R01 CA190121, Cancer Prevention & Research Institute of Texas (CPRIT) grant number R140606, and the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center to R.G.W.V.; grant number R01 CA163722 and TCGA contract number 28×S100 to E.G.V.M.; grant number CA143883 (MD Anderson Genome Data Analysis Center) to J.N.W.; and contract number HHSN261201000057C for A.E.S., M.L.C., and J.S.B.; See publication for full funding statement.
• Keywords: COPY-NUMBER; Genetics & Heredity; TP53 MUTATIONS; Science & Technology; CIRCULAR BINARY SEGMENTATION; Biotechnology & Applied Microbiology; CELLS; DNA; CLONAL EVOLUTION; Life Sciences & Biomedicine; BREAST CANCERS; MALIGNANT GLIOMAS; INTRATUMOR HETEROGENEITY; Biochemistry & Molecular Biology; LEUKEMIA
• Research Categories: Biology, Bioinformatics; Health Sciences, Pathology

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.