Extended Data Fig. 6: Treatment-associated mutations occur late in tumor development.

a, Pairs of biopsies of the same patient taken before the start and during or after treatment are represented as a dashed line. The upward trajectory of patients treated longer supports the conclusion that the signatures associated to treatments through the regression are indeed the mutational footprint of the therapies. Dots correspond to tumors of organs of origin colored as in Fig. 1b. b, Mutations of SigProfiler-extracted signatures associated to treatments are enriched for later substitutions. Dots correspond to tumors of organs of origin colored as in Fig. 1b. c, Mutations of SigProfiler-extracted signatures associated to treatments are enriched for subclonal substitutions. Dots correspond to tumors of organs of origin colored as in Fig. 1b. d, Comparison (one-tailed Mann-Whitney test) of the number of treatment-related mutations (according to SigProfiler) contributed by different drugs between short-exposure and long-exposure tumors, as in Fig. 2d. Dots correspond to tumors of organs of origin colored as in Fig. 1b. e, Comparison (one-tailed Mann-Whitney test) of the number of mutations contributed by different drugs between short-exposure and long-exposure tumors, as in Fig. 2d. In this figure only tumors from patients whose treatment duration is not estimated by clinicians, but rather exactly recorded in charts are included. f, g The mutation load contributed by the aging signature (f, SignatureAnalyzer; g, SigProfiler) does not correlate with the time of exposure to treatments.