Overview of rearrangements, CNAs, SNVs, SHM and focal deletions detected. (A) Inner arcs represent somatic rearrangements from each of the patient genomes, with a different color depicting each case. Cumulative summaries of all the somatic CNAs detected across all 96 cases are depicted in blue (deleted regions) and red (amplified regions). SHM targets identified from these genomes²²  are indicated with blue circles with diameter proportional to the number of mutated cases. (B) Small deletions are often not detectable by copy number analysis methods. Our de novo assembly-based pipeline identified breakpoints representing small deletions (indicated by blue bars), some of which affected a single gene. Two cases were found to have such deletions affecting ETV6. Of note, a fusion involving ETV6 and the immunoglobulin heavy chain locus was observed in a separate case. Deletions affecting other genes likely to be relevant to DLBCL are also shown. FHIT, with a focal deletion shown here, was also a common target of larger deletions by CNA analysis. S1PR2 was also a significant target of somatic point mutations and functionally cooperates with proteins encoded by GNA13 and GNAI2 (“Discussion”). The 2 deletions affecting TP63 in a single case are also shown (see supplemental Figure 12). The upper 3 transcripts represent TA isoforms, whereas the lower 2 correspond to Δ N isoforms. UTX is a histone demethylase that acts on H3K27, the same lysine targeted by EZH2, which is a target of activating mutations in NHL. A recently described small molecule inhibitor of EZH2 activity showed efficacy in DLBCL cell lines with UTX mutations.³¹