Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution.
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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. |
Year of Publication | 2015
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Journal | Genome Res
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Volume | 25
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Issue | 3
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Pages | 316-27
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Date Published | 2015 Mar
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ISSN | 1549-5469
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URL | |
DOI | 10.1101/gr.180612.114
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PubMed ID | 25650244
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PubMed Central ID | PMC4352879
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Grant list | P50 CA083639-12 / CA / NCI NIH HHS / United States
R01 CA188228 / CA / NCI NIH HHS / United States
R01 CA086335 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
HHSN261201000057C / CA / NCI NIH HHS / United States
R01 CA190121 / CA / NCI NIH HHS / United States
R25 CA094186 / CA / NCI NIH HHS / United States
CA143883 / CA / NCI NIH HHS / United States
CA016672 / CA / NCI NIH HHS / United States
HHSN261201000057I / CA / NCI NIH HHS / United States
P30 CA138292 / CA / NCI NIH HHS / United States
HHSN261201000057C / PHS HHS / United States
P50 CA083639 / CA / NCI NIH HHS / United States
U24 CA143883 / CA / NCI NIH HHS / United States
R01 CA163722 / CA / NCI NIH HHS / United States
P50 CA127001 / CA / NCI NIH HHS / United States
P01 CA085878 / CA / NCI NIH HHS / United States
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