Fig. 1: The mutational footprint of chemotherapies across treatment-related AMLs.

a Cancer patients (breast cancer as an example in the figure—purple circle) exposed to chemotherapy, which damages cell DNA (orange stars), may develop treatment related acute myeloid leukemia (tAMLs). Non-malignant hematopoietic cells at the time of exposure to chemotherapy are faced with a bottleneck that reduces the population, leading to the development of AML over time. b The whole-genome sequence of thirty tAML cases of patients who suffered from a primary solid tumor and were treated with different anticancer drugs (represented in the Sankey diagram) were obtained from three different sources, including three cases sequenced in-house. These were analyzed in combination with 32 cases of primary AMLs (WGS AML cohort). c Burden of single nucleotide variants and indels do not significantly differ across cases of the WGS AML cohort (two-tailed Mann–Whitney p = 0.33, and 0.1 respectively). d Mutational profile of a platinum-related signature active across cases in the WGS AML cohort. All tAML cases from patients exposed to platinum-related drugs exhibit activity of the signature (two-tailed Mann–Whitney p = 3.37 × 10⁻⁹, and 4.16 × 10⁻⁷). As a result of the process of reconstruction of the mutational profile of all samples carried out by the signatures extraction algorithm, one tAML case in a patient not exposed to platinum-based drugs and one primary AML case exhibit a “false” small activity of the platinum-related signature, a phenomenon known as signature bleeding²⁶. (See more details in Fig. S1.) e Burden of single nucleotide variants (left) and double base substitutions (right) of primary AML, non-platinum-exposed, and platinum-exposed tAML cases in the WGS AML cohort. Comparisons were carried out with a two-tailed Mann-Whitney test. f Number of mutations contributed by the platinum-related signature across tAML cases in comparison with that counted across metastatic tumors from several organs of origin. The box in each boxplot delimits the first and third quartiles of the distribution (with a line representing the median); the whiskers delimit the lowest data point above the first quartile minus 1.5 times the interquartile distance and the highest data point below the third quartile plus 1.5 times the interquartile distance. AML acute myeloid leukemia, t-AML treatment-related AML, WGS whole-genome sequencing, SBS single base substitution, SNV single nucleotide variant, INDEL insertion or deletion.