title: Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.
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 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.
authors: Department of Oncology, University of Cambridge, Cambridge CB2 2XZ, United Kingdom.
authors: Andrea
authors: A
authors: Sottoriva
authors: Inmaculada
authors: I
authors: Spiteri
authors: Sara G M
authors: SG
authors: Piccirillo
authors: Anestis
authors: A
authors: Touloumis
authors: V Peter
authors: VP
authors: Collins
authors: John C
authors: JC
authors: Marioni
authors: Christina
authors: C
authors: Curtis
authors: Colin
authors: C
authors: Watts
authors: Simon
authors: S
authors: Tavaré
mesh_terms: D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D019143:Evolution, Molecular; D018773:Genes, erbB-1; D019942:Genes, p16; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D010802:Phylogeny; D059467:Transcriptome
chemical_list: D004273:DNA, Neoplasm