Mutations affecting GNA13 in a large cohort of DLBCLs. Guided by the prevalence of GNA13 mutations in our DLBCL cohorts analyzed by RNA-seq and WGS, we sought to ascertain the full mutational landscape of this gene across a large number of de novo DLBCL cases (n = 279), of which 182 had been classified as GCB or non-GCB using immunohistochemistry.³⁰  (A) Nonsilent SNVs, indels, or splice site mutations were detected in a total of 40 patients (14.3%), with many cases harboring more than a single mutation. Up to five nonsilent mutations affecting GNA13 were observed in one patient. Overall, multiple truncation inducing mutations including frameshift indels and introduced stop codons were observed. The ratio of transitions to transversions and the large number of mutations affecting the WRCY/RGYW motif is consistent with AID-mediated mutation; however, there was no observable enrichment of mutations in the 5ʹ end of the locus (supplemental Table 5). In agreement with our previous observation, GNA13 mutations were strongly enriched in GCB, with 29 of 89 GCB (32.6%) cases having at least a single mutation in this gene and only 2 of 91 non-GCB cases mutated. (B) We mapped each of the mutations to the solved structure of Galpha13 (PDB accession no. 3AB3) and observed some nonsynonymous mutations in close proximity to the catalytic site (C), including multiple residues that interact directly with the substrate (GTP). Taken in conjunction with the prevalence of truncating mutations, we predict these likely inhibit the signaling activity of Gα₁₃.