APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types

Jakobsdottir, G. Maria, Brewer, Daniel S., Cooper, Colin, Green, Catherine and Wedge, David C. (2022) APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types. BMC Biology, 20. ISSN 1741-7007

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Abstract

Background: The APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3) family of cytidine deaminases is responsible for two mutational signatures (SBS2 and SBS13) found in cancer genomes. APOBEC3 enzymes are activated in response to viral infection, and have been associated with increased mutation burden and TP53 mutation. In addition to this, it has been suggested that APOBEC3 activity may be responsible for mutations that do not fall into the classical APOBEC3 signatures (SBS2 and SBS13), through generation of double strand breaks.Previous work has mainly focused on the effects of APOBEC3 within individual tumour types using exome sequencing data. Here, we use whole genome sequencing data from 2451 primary tumours from 39 different tumour types in the Pan-Cancer Analysis of Whole Genomes (PCAWG) data set to investigate the relationship between APOBEC3 and genomic instability (GI). Results and conclusions: We found that the number of classical APOBEC3 signature mutations correlates with increased mutation burden across different tumour types. In addition, the number of APOBEC3 mutations is a significant predictor for six different measures of GI. Two GI measures (INDELs attributed to INDEL signatures ID6 and ID8) strongly suggest the occurrence and error prone repair of double strand breaks, and the relationship between APOBEC3 mutations and GI remains when SNVs attributed to kataegis are excluded. We provide evidence that supports a model of cancer genome evolution in which APOBEC3 acts as a causative factor in the development of diverse and widespread genomic instability through the generation of double strand breaks. This has important implications for treatment approaches for cancers that carry APOBEC3 mutations, and challenges the view that APOBECs only act opportunistically at sites of single stranded DNA.

Item Type: Article
Additional Information: Funding: This work was supported by the Wellcome Trust (203852/Z/16/A). The research was also supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z with funding from the NIHR Oxford BRC. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Availability of data and materials: The data sets generated and/or analysed during the current study are available to download from https://dcc.icgc.org/releases/PCAWG
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 25 May 2022 08:30
Last Modified: 02 Jul 2022 00:18
URI: https://ueaeprints.uea.ac.uk/id/eprint/85151
DOI: 10.1186/s12915-022-01316-0

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