Prospectively defined patterns of APOBEC3A mutagenesis are prevalent in human cancers
Rachel A. DeWeerd,
Eszter Németh,
Ádám Póti,
Nataliya Petryk,
Chun-Long Chen,
Olivier Hyrien,
Dávid Szüts,
Abby M. Green
Affiliations
Rachel A. DeWeerd
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
Eszter Németh
Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
Ádám Póti
Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
Nataliya Petryk
Epigenetics & Cell Fate UMR7216, CNRS, University of Paris, 35 rue Hélène Brion, 75013 Paris, France
Chun-Long Chen
Institut Curie, Université PSL, Sorbonne Université, CNRS UMR3244, Dynamics of Genetic Information, Paris, France
Olivier Hyrien
Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, Université PSL, 46 rue d’Ulm, 75005 Paris, France
Dávid Szüts
Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary; Corresponding author
Abby M. Green
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA; Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; Corresponding author
Summary: Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. Two prevalent mutational patterns in human cancers are attributed to the APOBEC3 cytidine deaminase enzymes. Among the seven human APOBEC3 proteins, APOBEC3A is a potent deaminase and proposed driver of cancer mutagenesis. In this study, we prospectively examine genome-wide aberrations by expressing human APOBEC3A in avian DT40 cells. From whole-genome sequencing, we detect hundreds to thousands of base substitutions per genome. The APOBEC3A signature includes widespread cytidine mutations and a unique insertion-deletion (indel) signature consisting largely of cytidine deletions. This multi-dimensional APOBEC3A signature is prevalent in human cancer genomes. Our data further reveal replication-associated mutations, the rate of stem-loop and clustered mutations, and deamination of methylated cytidines. This comprehensive signature of APOBEC3A mutagenesis is a tool for future studies and a potential biomarker for APOBEC3 activity in cancer.
