TY - JOUR
T1 - Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response
AU - Hernández-Verdin, Isaias
AU - Akdemir, Kadir C.
AU - Ramazzotti, Daniele
AU - Caravagna, Giulio
AU - Labreche, Karim
AU - Mokhtari, Karima
AU - Hoang-Xuan, Khê
AU - Peyre, Matthieu
AU - Bielle, Franck
AU - Touat, Mehdi
AU - Idbaih, Ahmed
AU - Duval, Alex
AU - Sanson, Marc
AU - Alentorn, Agustí
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41698-022-00331-2
DO - 10.1038/s41698-022-00331-2
M3 - Article
C2 - 36456685
AN - SCOPUS:85143229189
SN - 2397-768X
VL - 6
JO - npj Precision Oncology
JF - npj Precision Oncology
IS - 1
M1 - 89
ER -