PMID- 23412337
OWN - NLM
STAT- MEDLINE
DCOM- 20130502
LR  - 20220410
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 10
DP  - 2013 Mar 5
TI  - Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary 
      dynamics.
PG  - 4009-14
LID - 10.1073/pnas.1219747110 [doi]
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 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.
FAU - Sottoriva, Andrea
AU  - Sottoriva A
AD  - Department of Oncology, University of Cambridge, Cambridge CB2 2XZ, United 
      Kingdom.
FAU - Spiteri, Inmaculada
AU  - Spiteri I
FAU - Piccirillo, Sara G M
AU  - Piccirillo SG
FAU - Touloumis, Anestis
AU  - Touloumis A
FAU - Collins, V Peter
AU  - Collins VP
FAU - Marioni, John C
AU  - Marioni JC
FAU - Curtis, Christina
AU  - Curtis C
FAU - Watts, Colin
AU  - Watts C
FAU - Tavare, Simon
AU  - Tavare S
LA  - eng
GR  - C14303/A10825/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130214
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA, Neoplasm)
SB  - IM
MH  - Base Sequence
MH  - Brain Neoplasms/*genetics
MH  - Chromosome Aberrations
MH  - DNA Copy Number Variations
MH  - DNA, Neoplasm/genetics
MH  - Disease Progression
MH  - Evolution, Molecular
MH  - Genes, erbB-1
MH  - Genes, p16
MH  - Glioblastoma/*genetics
MH  - Humans
MH  - Phylogeny
MH  - Transcriptome
PMC - PMC3593922
COIS- The authors declare no conflict of interest.
EDAT- 2013/02/16 06:00
MHDA- 2013/05/03 06:00
PMCR- 2013/02/14
CRDT- 2013/02/16 06:00
PHST- 2013/02/16 06:00 [entrez]
PHST- 2013/02/16 06:00 [pubmed]
PHST- 2013/05/03 06:00 [medline]
PHST- 2013/02/14 00:00 [pmc-release]
AID - 1219747110 [pii]
AID - 201219747 [pii]
AID - 10.1073/pnas.1219747110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14. doi: 
      10.1073/pnas.1219747110. Epub 2013 Feb 14.