Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics

Andrea Sottoriva, Inmaculada Spiteri, Sara G.M. Piccirillo, Anestis Touloumis, V. Peter Collins, John C. Marioni, Christina Curtis, Colin Watts, Simon Tavaré

Research output: Contribution to journalArticlepeer-review

836 Scopus citations

Abstract

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, detectingmultiple 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.

Original languageEnglish (US)
Pages (from-to)4009-4014
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number10
DOIs
StatePublished - Mar 5 2013

Keywords

  • High grade glioma
  • Tumor progression

ASJC Scopus subject areas

  • General

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