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

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

doi:10.1038/s41698-022-00331-2

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

NPJ Precis Oncol. 2022 Dec 1;6(1):89. doi: 10.1038/s41698-022-00331-2.

Authors

Isaias Hernández-Verdin¹, Kadir C Akdemir², Daniele Ramazzotti³, Giulio Caravagna⁴, Karim Labreche¹, Karima Mokhtari^{1

5

6}, Khê Hoang-Xuan^{1

7}, Matthieu Peyre^{1

8}, Franck Bielle^{1

5

6}, Mehdi Touat^{1

7}, Ahmed Idbaih^{1

7}, Alex Duval^{9

10}, Marc Sanson^{1

6

7}, Agustí Alentorn^{11

12}

Affiliations

¹ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
² Departments of Genomic Medicine and Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy.
⁴ Cancer Data Science Laboratory, Dipartimento di Matematica e Geoscienze, Università degli Studi di Trieste, Trieste, Italy.
⁵ Department of Neuropathology, Pitié Salpêtrière-Charles Foix, Paris, France.
⁶ Onconeurotek, AP-HP, Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
⁷ Department of Neurology-2, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁸ Department of Neurosurgery, AP-HP, Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
⁹ Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.
¹⁰ Sorbonne Université, Genetics Department, AP-HP.Sorbonne Université, hospital Pitié-Salpêtrière, F-75012, Paris, France.
¹¹ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. agusti.alentorn@icm-institute.org.
¹² Department of Neurology-2, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. agusti.alentorn@icm-institute.org.

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.

Abstract

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