Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome, or targeted sequencing. AID mutations are present at pan-cancer level with higher frequency in hematological cancers and higher presence at transcriptionally active TAD domains. AID synergizes initial hotspot mutations by a second composite mutation. AID mutational load was found to be independently associated with a favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2000 samples. Finally, we found that AID-related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity, and T-cell exhaustion, which may increase ICI sensitivity.

Hernández-Verdin, I., Akdemir, K., Ramazzotti, D., Caravagna, G., Labreche, K., Mokhtari, K., et al. (2022). Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response. NPJ PRECISION ONCOLOGY, 6(1) [10.1038/s41698-022-00331-2].

Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response

Daniele Ramazzotti;
2022

Abstract

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome, or targeted sequencing. AID mutations are present at pan-cancer level with higher frequency in hematological cancers and higher presence at transcriptionally active TAD domains. AID synergizes initial hotspot mutations by a second composite mutation. AID mutational load was found to be independently associated with a favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2000 samples. Finally, we found that AID-related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity, and T-cell exhaustion, which may increase ICI sensitivity.
Articolo in rivista - Articolo scientifico
Cancer; Mutational signatures; APOBEC; ICI response
English
1-dic-2022
2022
6
1
89
open
Hernández-Verdin, I., Akdemir, K., Ramazzotti, D., Caravagna, G., Labreche, K., Mokhtari, K., et al. (2022). Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response. NPJ PRECISION ONCOLOGY, 6(1) [10.1038/s41698-022-00331-2].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/398231
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