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A. Agraz-Doblas et al.
instability of leukemic clones surviving induction/consoli- dation chemotherapy. This is further reflected by a signif- icant enrichment of signature 6 associated with defective DNA mismatch repair, including a higher number of small indels, observed in MLL-AF4+ patients at relapse (Online Supplementary Figure S6A).
nosis to relapse, we performed high-coverage targeted sequencing on the identified mutations in paired diagnos- tic-remission-relapse samples.37 Importantly, the main leukemic clone at relapse was always present at diagnosis although in some cases with a very low MAF, suggesting a chemotherapy-induced clonal pressure selecting for resistant/adapted leukemic subclones (Figure 3C).
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To delineate the evolutionary clonal structure from diag-
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Figure 3. Clonal evolution and genomic instability at relapse. (A) Total number of mutations identified for each patient in paired diagnostic- relapse samples. Total number of non-synonymous mutations (yellow area, right Y axis) and mutant allele frequency (MAF) for each mutation (individual dots, left Y axis) are repre- sented for paired diagnostic and relapsed (R) samples. (B) Circos plot representation of the total number of mutations identified at diagnosis and relapse for a representative patient (MA4_17). Genomic rearrangements are represented by lines connecting both breakpoints. Copy number alter- ations (blue=gains, red=losses) are represented by the outer gray circle. Somatic mutations (both single nucleotide variants and indels) are depicted in the center of the circle and the affected gene is indicated. (C) Graphic representation of clonal evo- lution in paired diagnostic (DX)- relapsed (RL) samples. The number of unique somatic mutations called at diagnosis (orange), relapse (yellow) or shared between DX and REL (red) are indicated. Bigger gene names indicate higher MAF for the mutations shared at DX and REL. (D) Dynamics of RAS- mutated clones identified as MAF in matched DX-Remission-REL trios (n=8).
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