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Nat Med. 2016 Jan;22(1):105-13. doi: 10.1038/nm.3984. Epub 2015 Nov 30.

Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.

Author information

1
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
2
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
3
Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
4
Center for Evolution and Cancer, University of California San Francisco, San Francisco, California, USA.
5
Department of Psychology, Arizona State University, Tempe, Arizona, USA.
6
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
7
Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
8
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA.
9
Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
10
Centre for Evolution and Cancer, Institute for Cancer Research, London, UK.
11
Biodesign Institute, Arizona State University, Tempe, Arizona, USA.

Abstract

Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.

PMID:
26618723
PMCID:
PMC4830693
DOI:
10.1038/nm.3984
[Indexed for MEDLINE]
Free PMC Article
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