@misc{10481/91335,
year = {2024},
month = {2},
url = {https://hdl.handle.net/10481/91335},
abstract = {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.},
organization = {Grant PID2021-126111OB-I00 funded by
the MCIN/AEI/10.13039/501100011033},
organization = {ERDF A way to make Europe},
organization = {Junta de Andalucía (grants PI-0135–2020, and P20_00688)},
organization = {Spanish
Association for Cancer Research (LABORATORY-AECC-2018)},
organization = {FPU19/00576 predoctoral fellowship funded by the Spanish
Ministry of Science, Innovation, and Universities},
publisher = {Springer Nature},
keywords = {B-cell lymphoma},
keywords = {Somatic hypermutation},
keywords = {Splicing mutations},
title = {Activation‑induced cytidine deaminase causes recurrent splicing mutations in diffuse large B‑cell lymphoma},
doi = {10.1186/s12943-024-01960-w},
author = {Benítez Cantos, María Soledad and Cano Gutiérrez, Carlos and Cuadros Celorrio, Marta Eugenia and Medina Vico, Pedro Pablo},
}