Activation‑induced cytidine deaminase causes recurrent splicing mutations in diffuse large B‑cell lymphoma Benítez Cantos, María Soledad Cano Gutiérrez, Carlos Cuadros Celorrio, Marta Eugenia Medina Vico, Pedro Pablo B-cell lymphoma Somatic hypermutation Splicing mutations The online version contains supplementary material available at https://doi.org/10. 1186/s12943-​024-​01960-w. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma. A major mutagenic process in DLBCL is aberrant somatic hypermutation (aSHM) by activation-induced cytidine deaminase (AID), which occurs preferentially at RCH/TW sequence motifs proximal to transcription start sites. Splice sequences are highly conserved, rich in RCH/TW motifs, and recurrently mutated in DLBCL. Therefore, we hypothesized that aSHM may cause recurrent splicing mutations in DLBCL. In a meta-cohort of > 1,800 DLBCLs, we found that 77.5% of splicing mutations in 29 recurrently mutated genes followed aSHM patterns. In addition, in whole-genome sequencing (WGS) data from 153 DLBCLs, proximal mutations in splice sequences, especially in donors, were significantly enriched in RCH/TW motifs (p < 0.01). We validated this enrichment in two additional DLBCL cohorts (N > 2,000; p < 0.0001) and confirmed its absence in 12 cancer types without aSHM (N > 6,300). Comparing sequencing data from mouse models with and without AID activity showed that the splice donor sequences were the top genomic feature enriched in AID-induced mutations (p < 0.0001). Finally, we observed that most AID-related splice site mutations are clonal within a sample, indicating that aSHM may cause early loss-of-function events in lymphomagenesis. Overall, these findings support that AID causes an overrepresentation of clonal splicing mutations in DLBCL. 2024-05-02T11:35:26Z 2024-05-02T11:35:26Z 2024-02-24 journal article Benitez-Cantos, M.S., Cano, C., Cuadros, M. et al. Activation-induced cytidine deaminase causes recurrent splicing mutations in diffuse large B-cell lymphoma. Mol Cancer 23, 42 (2024). [https://doi.org/10.1186/s12943-024-01960-w] https://hdl.handle.net/10481/91335 10.1186/s12943-024-01960-w eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Springer Nature