TY - JOUR
T1 - Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics
AU - Sottoriva, Andrea
AU - Spiteri, Inmaculada
AU - Piccirillo, Sara G.M.
AU - Touloumis, Anestis
AU - Collins, V. Peter
AU - Marioni, John C.
AU - Curtis, Christina
AU - Watts, Colin
AU - Tavaré, Simon
PY - 2013/3/5
Y1 - 2013/3/5
N2 - 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.
AB - 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.
KW - High grade glioma
KW - Tumor progression
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U2 - 10.1073/pnas.1219747110
DO - 10.1073/pnas.1219747110
M3 - Article
C2 - 23412337
AN - SCOPUS:84874598318
SN - 0027-8424
VL - 110
SP - 4009
EP - 4014
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -