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. 2017 Dec 19;8:2193. doi: 10.1038/s41467-017-02320-7

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© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — Intratumoral heterogeneity association with overall survival. a Overall survival of high and low pre-treatment intratumoral heterogeneity. We defined heterogeneity as the proportion of mutations per pre-treatment tumor that were inferred to be subclonal. In Cox proportional hazards analysis, pre-treatment heterogeneity was statistically significantly associated with overall survival (Cox PH: HRR 1.50 (95% CI 1.01–2.23), p = 0.046). Dividing the cohort above and below a cutoff of 20% of subclonal mutations (n = 16/14 low/high heterogeneity tumors, Supplementary Fig. 12a) resulted in a trend towards improved survival for pts with low pre-treatment heterogeneity (log-rank p = 0.088). b Overall survival of high and low post-treatment intratumoral heterogeneity. We defined heterogeneity as the proportion of mutations per post-treatment tumor that were inferred to be subclonal. In Cox proportional hazards analysis, post-treatment heterogeneity was negatively associated with overall survival (HRR 1.89 (95% CI 1.1–3.1), p = 0.013), and dividing the cohort above and below a cutoff of 20% of subclonal mutations (n = 16/14 low/high heterogeneity tumors, Supplementary Fig. 12b) resulted in improved survival for pts those with low post-treatment heterogeneity (log-rank p = 0.04). c Overall survival of high and low heterogeneity tumors. We defined heterogeneity as the number of inferred subclones (Methods), which includes shared subclones and subclones private to either the pre-treatment or post-treatment tumor. The number of subclones was negatively associated with overall survival (Cox PH: HRR 1.64 (95% CI 1.08–2.49), p = 0.02), and using a threshold of 6 clones (n = 15/15 with high/low heterogeneity as defined, Supplementary Fig. 12c) demonstrates improved survival for patients with low heterogeneity (log rank p = 0.004)