Hernández-Verdin Isaias, Akdemir Kadir C, Ramazzotti Daniele, Caravagna Giulio, Labreche Karim, Mokhtari Karima, Hoang-Xuan Khê, Peyre Matthieu, Bielle Franck, Touat Mehdi, Idbaih Ahmed, Duval Alex, Sanson Marc, Alentorn Agustí
Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
Departments of Genomic Medicine and Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
NPJ Precis Oncol. 2022 Dec 1;6(1):89. doi: 10.1038/s41698-022-00331-2.
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.
活化诱导的胞苷脱氨酶（AICDA 或 AID）是免疫球蛋白体细胞超突变和类别转换重组的驱动因素。此外，这种属于载脂蛋白 B 编辑酶催化多肽样家族（APOBEC 家族）的脱氨酶可能在全基因组范围内产生脱靶效应，但其在泛癌水平上的作用尚未得到充分阐明。在这里，我们使用了不同的泛癌数据集，通过全基因组、全外显子组或靶向测序总共分析了超过 50000 个样本。AID 突变在泛癌水平上存在，在血液系统癌症中频率更高，在转录活跃的拓扑相关结构域（TAD）中出现频率更高。AID 通过第二次复合突变协同作用于初始热点突变。在分析了 2000 个样本后，发现 AID 突变负荷与接受免疫检查点抑制剂（ICI）治疗的所有癌症患者的良好预后独立相关。最后，我们发现，与其他突变特征相比，由更频繁热点处的突变产生的与 AID 相关的新表位增强了 CXC 趋化因子配体 13（CXCL13）/C-C 趋化因子受体 5（CCR5）的表达、免疫原性和 T 细胞耗竭，这可能会增加 ICI 敏感性。
