期刊
NPJ PRECISION ONCOLOGY
卷 6, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41698-022-00331-2
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资金
- Investissements d'avenir
- French National Research Agency [INCa-DGOS-Inserm_12560, ANR-10-IAIHU-06, 2017-1-RT-04, ANR-18-RHUS-0012]
- RAM foundation
- ARTC foundation
- Bristol Myers Squibb (BMS) [RDON06618]
- MSD Avenir
- Bicocca 2020 Starting Grant
- Premio Giovani Talenti dell'Universita degli Studi di Milano-Bicocca
- Agence Nationale de la Recherche (ANR) [ANR-18-RHUS-0012] Funding Source: Agence Nationale de la Recherche (ANR)
This study reveals the presence of AID mutations at the pan-cancer level, with higher frequency in hematological cancers. AID mutational load is independently associated with a favorable outcome in immune-checkpoint inhibitors treated patients. Additionally, AID-related neoepitopes enhance immunogenicity and increase ICI sensitivity.
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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