Activation‑induced cytidine deaminase causes recurrent splicing mutations in diffuse large B‑cell lymphoma
Metadatos
Mostrar el registro completo del ítemAutor
Benítez Cantos, María Soledad; Cano Gutiérrez, Carlos; Cuadros Celorrio, Marta Eugenia; Medina Vico, Pedro PabloEditorial
Springer Nature
Materia
B-cell lymphoma Somatic hypermutation Splicing mutations
Fecha
2024-02-24Referencia bibliográfica
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]
Patrocinador
Grant PID2021-126111OB-I00 funded by the MCIN/AEI/10.13039/501100011033; ERDF A way to make Europe; Junta de Andalucía (grants PI-0135–2020, and P20_00688); Spanish Association for Cancer Research (LABORATORY-AECC-2018); FPU19/00576 predoctoral fellowship funded by the Spanish Ministry of Science, Innovation, and UniversitiesResumen
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.