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

Noemi Andor, Trevor A. Graham, Marnix Jansen, Li C. Xia, C Athena Aktipis, Claudia Petritsch, Hanlee P. Ji, Carlo Maley

Research output: Contribution to journalArticle

232 Citations (Scopus)

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 â ‰1 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 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.

Original languageEnglish (US)
Pages (from-to)105-113
Number of pages9
JournalNature Medicine
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2016

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Tumors
Clone Cells
Neoplasms
Genes
Genomic Instability
Bioinformatics
Genome
Exome
Genetic Heterogeneity
Atlases
Ploidies
Computational Biology
Gene Frequency
Cost-Benefit Analysis
Costs
Mortality

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. / Andor, Noemi; Graham, Trevor A.; Jansen, Marnix; Xia, Li C.; Aktipis, C Athena; Petritsch, Claudia; Ji, Hanlee P.; Maley, Carlo.

In: Nature Medicine, Vol. 22, No. 1, 01.01.2016, p. 105-113.

Research output: Contribution to journalArticle

Andor, N, Graham, TA, Jansen, M, Xia, LC, Aktipis, CA, Petritsch, C, Ji, HP & Maley, C 2016, 'Pan-cancer analysis of the extent and consequences of intratumor heterogeneity', Nature Medicine, vol. 22, no. 1, pp. 105-113. https://doi.org/10.1038/nm.3984
Andor, Noemi ; Graham, Trevor A. ; Jansen, Marnix ; Xia, Li C. ; Aktipis, C Athena ; Petritsch, Claudia ; Ji, Hanlee P. ; Maley, Carlo. / Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. In: Nature Medicine. 2016 ; Vol. 22, No. 1. pp. 105-113.
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