Evolution of mutational signatures from diagnosis to relapse. (A) Contribution of known COSMIC signatures and 2 novel relapse-specific signatures to somatic SNVs identified in the matched diagnostic (top) or relapse (bottom) samples of patients in the 3 relapse time categories. Samples are sorted according to increasing relapse time from left to right. Relapse-specific mutations in DNA mismatch repair genes (ie, MSH2, MSH6, or PMS2) are indicated at bottom; samples with bi-allelic mutations are marked by a star. MMR indicates mismatch repair deficiency-associated signatures. (B) Trinucleotide mutation spectra of novel signatures A and B, with the contexts of selected example relapse-specific gene variants indicated.