Figure 5.
Causes and consequences of the 2 novel mutational signatures. (A) Detection of novel signatures in additional cohorts of primarily diagnosis (black text) or relapse (blue text) samples. Number of tumor samples is indicated in parentheses. Heatmap at bottom depicts percentage of patients receiving indicated therapy in the relapsed cohort. anthracyc., anthracyclines; cyclophosph., cyclophosphamide; thiop., thiopurines; metho., methotrexate. P is by Fisher’s exact test. PCAWG, Pan-Cancer Analysis of Whole Genomes. Shanghai refers to our cohort. Asterisk indicates that a subset of relapsed AMLs from TARGET (14 of 95) received thiopurines but only for ≤2 weeks, an insufficient time to generate the signature as shown in panel B, as part of the CCG-2961 trial. (B) Left, correlation between relapse time and novel signature B strength. Blue indicates approximate time periods of thiopurine treatment in 17 cases for which detailed clinical information was available; treatment end is indicated as 3 years as all patients ended treatment by that time (see supplemental Methods); r is Pearson correlation coefficient excluding novel signature A/B–positive (double-positive) cases (2 red points), which are also excluded from the indicated regression line. Right, TPMT expression based on RNA-Seq of diagnosis samples of novel signature B–negative or signature B–positive patients; P value is by 2-sample Student t test. (C) Mutational spectra of two MCF10A single-cell clones after treatment with 6-thioguanine 10 nM for 7 weeks. The y-axis represents the number of mutations in the treated clone minus the background mutation spectra averaged from 2 untreated single-cell clones. Bottom shows novel signature B; “cosine” indicates cosine similarity for indicated comparisons, and "prop. SNVs" indicates proportion of SNVs. Light vertical lines mark novel signature B–preferred trinucleotide mutation types for comparison. (D) Relapse-specific pathogenic mutations with ≥50% probability to be caused by the novel signatures at relapse. The y-axis represents the probability each variant was caused by a given signature, and each variant represents a relapse-specific mutation detected in a specific patient. Mutations in the same patient are shown as rectangles joined by lines (top). “S261 sp” represents a TP53 variant (chr17:7 577 157, T>G) likely affecting splicing, and the T125T variant also affects splicing.

Causes and consequences of the 2 novel mutational signatures. (A) Detection of novel signatures in additional cohorts of primarily diagnosis (black text) or relapse (blue text) samples. Number of tumor samples is indicated in parentheses. Heatmap at bottom depicts percentage of patients receiving indicated therapy in the relapsed cohort. anthracyc., anthracyclines; cyclophosph., cyclophosphamide; thiop., thiopurines; metho., methotrexate. P is by Fisher’s exact test. PCAWG, Pan-Cancer Analysis of Whole Genomes. Shanghai refers to our cohort. Asterisk indicates that a subset of relapsed AMLs from TARGET (14 of 95) received thiopurines but only for ≤2 weeks, an insufficient time to generate the signature as shown in panel B, as part of the CCG-2961 trial. (B) Left, correlation between relapse time and novel signature B strength. Blue indicates approximate time periods of thiopurine treatment in 17 cases for which detailed clinical information was available; treatment end is indicated as 3 years as all patients ended treatment by that time (see supplemental Methods); r is Pearson correlation coefficient excluding novel signature A/B–positive (double-positive) cases (2 red points), which are also excluded from the indicated regression line. Right, TPMT expression based on RNA-Seq of diagnosis samples of novel signature B–negative or signature B–positive patients; P value is by 2-sample Student t test. (C) Mutational spectra of two MCF10A single-cell clones after treatment with 6-thioguanine 10 nM for 7 weeks. The y-axis represents the number of mutations in the treated clone minus the background mutation spectra averaged from 2 untreated single-cell clones. Bottom shows novel signature B; “cosine” indicates cosine similarity for indicated comparisons, and "prop. SNVs" indicates proportion of SNVs. Light vertical lines mark novel signature B–preferred trinucleotide mutation types for comparison. (D) Relapse-specific pathogenic mutations with ≥50% probability to be caused by the novel signatures at relapse. The y-axis represents the probability each variant was caused by a given signature, and each variant represents a relapse-specific mutation detected in a specific patient. Mutations in the same patient are shown as rectangles joined by lines (top). “S261 sp” represents a TP53 variant (chr17:7 577 157, T>G) likely affecting splicing, and the T125T variant also affects splicing.

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