Timing of chromosomal duplications in DLBCL evolution. The sequence data can be used to approximate the relative time in which individual large amplifications/gains occurred during the evolution of the tumor. Here, the timing estimate for amplifications detected in each genome is shown for 5 chromosomes commonly affected by such events. The genomic coordinates amplifications are shown on the x-axis, with separate colors indicating events detected in different individuals. The y-axis shows the time at which the event was estimated to occur, with events near the bottom arising earlier in tumor development and those near the top arising later. Only events for which we could precisely calculate timing were included (confidence interval range < 0.2). Samples involving approximated REL amplifications are shown separately (supplemental Figure 17). Despite arising later in some cases, gains of 18 were nonetheless one of the earliest of all amplification events detected (supplemental Figure 18). The genes targeted by amplifications of 11q and 1q have not been conclusively identified. The position of ETS1 is indicated because it also a significant target of somatic point mutations in our data, and thus a potential novel oncogene. The region of overlap between the regions gained on 1q contains a small number of genes including IKBKE, which encodes IkappaB kinase ε, a positive regulator of RELA.38 Among the 96 DLBCL cases analyzed for CNAs, IKBKE expression was significantly higher in amplified cases (P = .00745, Wilcoxon Rank Sum test).
