Differential analysis of genome-wide mutational signatures. (A) From top to bottom: number of tumors with SBS signatures across the entire data set (dotted line represents combined ndMM and rrMM sample size) with signatures sorted left to right by descending count, number of mutations per sample (color representing groups) in respective signatures, differential activity of signatures between rrMM and ndMM with values in the positive direction showing enrichment in the rrMM cohort and vice versa, proportion of tumors carrying each signature in each cohort. (B) Heatmap of pairwise associations among SBS signatures as assessed by Fisher exact test. ORs are given for each pair and shades of red and blue colors represents statistically significant cooccurrence (OR > 1) and mutual exclusivity (0 < OR < 1) patterns, respectively, after multiple-testing correction (FDR < 0.05). Gray color indicates nonsignificant association regardless of OR value. (C) Lollipop plot of correlation coefficient values between the activity of each SBS signature and mutation burden in rrMM tumors. The length of the bars represents the Pearson R value and the size of the circles represents the log10 of the FDR-adjusted P value of the correlation (larger circles indicate higher significance). Colors of the signatures match those in supplemental Figure 10. (D) Shift in mutational signature activity between clonal and subclonal mutations for signatures displaying strong positive correlation with mutation burden in the rrMM cohort and SBS9 (hypermutation signature) for comparison. SBS12 shows a strong signal of subclonal increase, whereas SBS9 shows decrease across most tumors.