1. Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response
- Author
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Hernández-Verdin, I, Akdemir, K, Ramazzotti, D, Caravagna, G, Labreche, K, Mokhtari, K, Hoang-Xuan, K, Peyre, M, Bielle, F, Touat, M, Idbaih, A, Duval, A, Sanson, M, Alentorn, A, Isaias Hernández-Verdin, Kadir C. Akdemir, Daniele Ramazzotti, Giulio Caravagna, Karim Labreche, Karima Mokhtari, Khê Hoang-Xuan, Matthieu Peyre, Franck Bielle, Mehdi Touat, Ahmed Idbaih, Alex Duval, Marc Sanson, Agustí Alentorn, Hernández-Verdin, I, Akdemir, K, Ramazzotti, D, Caravagna, G, Labreche, K, Mokhtari, K, Hoang-Xuan, K, Peyre, M, Bielle, F, Touat, M, Idbaih, A, Duval, A, Sanson, M, Alentorn, A, Isaias Hernández-Verdin, Kadir C. Akdemir, Daniele Ramazzotti, Giulio Caravagna, Karim Labreche, Karima Mokhtari, Khê Hoang-Xuan, Matthieu Peyre, Franck Bielle, Mehdi Touat, Ahmed Idbaih, Alex Duval, Marc Sanson, and Agustí Alentorn
- 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.
- Published
- 2022