Prospectively defined patterns of APOBEC3A mutagenesis are prevalent in human cancers.

Abstract

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.

• Authors: Rachel A DeWeerd, Eszter Németh, Ádám Póti, Nataliya Petryk, Chun-Long Chen, Olivier Hyrien, Dávid Szüts, Abby M Green
• Journal: Cell reports (Cell Rep) Vol. 38 Issue 12 Pg. 110555 (03 22 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35320711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Proteins
• Cytidine
• APOBEC3A protein, human
• Cytidine Deaminase

Topics

• Cytidine
• Cytidine Deaminase
• Genome, Human
• Humans
• Mutagenesis
• Neoplasms (genetics)
• Proteins