Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 10, Pages 4009-4014Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1219747110
Keywords
tumor progression; high grade glioma
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Funding
- NIHR Cambridge Biomedical Research Centre
- Cancer Research UK [C14303/A10825]
- Addenbrooke's Charitable Trust
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Higher Education Funding Council for England
- Royal College of Surgeons of Edinburgh
- European Commission
- European Bioinformatics Institute
- Keck School of Medicine of the University of Southern California
- Cancer Research UK [19556] Funding Source: researchfish
- The Brain Tumour Charity [10/136] Funding Source: researchfish
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Glioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. To address this, we developed a unique surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB patients. We present an integrated genomic analysis that uncovers extensive intratumor heterogeneity, with most patients displaying different GB subtypes within the same tumor. Moreover, we reconstructed the phylogeny of the fragments for each patient, identifying copy number alterations in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as later events during cancer progression. We also characterized the clonal organization of each tumor fragment at the singlemolecule level, detecting multiple coexisting cell lineages. Our results reveal the genome-wide architecture of intratumor variability in GB across multiple spatial scales and patient-specific patterns of cancer evolution, with consequences for treatment design.
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