Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.
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Date
2013-03-05Author
Sottoriva, A
Spiteri, I
Piccirillo, SGM
Touloumis, A
Collins, VP
Marioni, JC
Curtis, C
Watts, C
Tavaré, S
Type
Journal Article
Metadata
Show full item recordAbstract
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 single-molecule 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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Subject
Humans
Glioblastoma
Brain Neoplasms
Chromosome Aberrations
Disease Progression
DNA, Neoplasm
Evolution, Molecular
Phylogeny
Base Sequence
Genes, p16
Genes, erbB-1
DNA Copy Number Variations
Transcriptome
Research team
Evolutionary Genomics & Modelling
Language
eng
License start date
2013-03
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2013, 110 (10), pp. 4009 - 4014
Publisher
NATL ACAD SCIENCES