RPS15 mutations in CLL. (A) Localization of SNVs detected by either WES or with targeted resequencing of exon 4 in the extension cohorts (data for each cohort are provided in supplemental Table 10). With the exception of a single mutation in amino acid 33 (not shown in figure), all mutations clustered to the C-terminal of the RPS15 protein. Exons are marked with dashed lines and the region covered in the targeted resequencing is color coded. (B) Frequency of RPS15 mutations in the FCR relapse cohort (n = 41), the extended screening cohort (n = 605), the CLL4 trial cohort (n = 329), in RS cases (n = 30) and IGHV-mutated/stage A patients (n = 185). (C-D) Concurrent mutations and genetic lesions in RPS15-mutated cases in the extended screening cohort and the UK CLL4 cohort. (E-F) Overall survival for subgroups carrying recurrent cytogenetic and molecular aberrations. Pairwise log-rank test: RPS15^mut vs del(13q), P < .001; RPS15^mut vs TP53^abn, P = .42; RPS15^mut/TP53^abn vs TP53^abn, P = .15; RPS15^mut vs RPS15^mut/TP53^abn, P = .12. Ten-year survival rate for RPS15^mut/TP53^wt was similar to RPS15^mut/TP53^abn and RPS15^wt/TP53^abn patients (0%, 0%, and 22%, respectively), but lower than the remaining RPS15^wt/TP53^wt patients (59%, see supplemental Figure 7). NA, not available.