title: Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
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.
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.|Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Noemi
authors.initials: N
authors.lastname: Andor
authors.affiliation: Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Trevor A
authors.identifier: http://orcid.org/0000-0001-9582-1597
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Li C
authors.identifier: http://orcid.org/0000-0003-0868-1923
authors.initials: LC
authors.lastname: Xia
authors.affiliation: Center for Evolution and Cancer, University of California San Francisco, San Francisco, California, USA.|Department of Psychology, Arizona State University, Tempe, Arizona, USA.
authors.forename: C Athena
authors.initials: CA
authors.lastname: Aktipis
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.|Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Petritsch
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.|Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
authors.forename: Hanlee P
authors.initials: HP
authors.lastname: Ji
authors.affiliation: Center for Evolution and Cancer, University of California San Francisco, San Francisco, California, USA.|Centre for Evolution and Cancer, Institute for Cancer Research, London, UK.|Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
authors.forename: Carlo C
authors.initials: CC
authors.lastname: Maley
mesh_terms: D053144:Cell Nucleus Shape / Q000235:genetics; D002999:Clone Cells; D019295:Computational Biology; D056915:DNA Copy Number Variations / Q000235:genetics; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality; D016016:Proportional Hazards Models