Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome. This study reports exome sequencing of samples from 538 individuals with chronic lymphocytic leukaemia (CLL), including 278 collected as part of a prospective clinical trial; recurrently mutated genes are identified and pathways involved in CLL are highlighted, as well as their evolution in progression and disease relapse. The results of whole-exome sequencing (WES) of samples from 538 individuals with chronic lymphocytic leukaemia (CLL), including 278 collected as part of a prospective clinical trial, identify recurrently mutated genes and highlight pathways involved in the cancer, including RNA processing and export, MYC activity and MAPK signalling. Comparisons of samples from before and after exposure to a uniform treatment demonstrate a high frequency of clonal evolution in individuals with disease relapse.

Mutations driving CLL and their evolution in progression and relapse