Fig. 4: Resolving uncertainty in mutational signature fitting.

A Bar chart showing the estimated SBS-MM1 contribution in 82 MM samples with and without prior melphalan exposure by mmsig (similar to Fig. 2B), with 95% CI estimated from 1000 bootstrapping iterations. Asterisks indicate statistically significant transcriptional strand bias in characteristic trinucleotide contexts (Poisson test p < 0.05). B Stached bar chart showing mutational signature profiles of 49 patients with acute myeloid leukemia (AML) with (n = 2, left) and without (n = 47, right) prior platinum exposure, estimated using deconstructSigs (top) and mmsig (bottom). SBS-HSPC is a mutational signature characteristic of hematopoietic stem cells. C Similar to A for 49 AML patients with and without prior platinum exposure. D Bar chart showing the number of mutations on the transcribed (blue) and untranscribed (red) strand in each trinucleotide context for three patients. On the top we show one patient who did not have prior history of platinum exposure, but where SBS35 was identified with the whole 95% CI above zero. The mutational signature profile does not fit the classic pattern of SBS35, however, and there is no sign of the characteristic transcriptional strand bias, suggesting a false positive call. The two lower panels show the patients with therapy-related AML who were exposed to platinum. Their mutational profiles are highly dominated by SBS35 with strong transcriptional strand bias.