The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other APOBEC3 family members, including APOBEC3B, fail to promote liver tumor formation. Tumor DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in human tumor datasets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.
Bibliographical noteFunding Information:
These studies were supported in part by the National Cancer Institute (grant P01CA234228 to R.S. Harris), the National Institute of Allergy and Infectious Diseases (grant R01AI085015 to S.R. Ross), the National Institute on Aging (grant R21AG047114 to S.R. Ross), the University of Minnesota College of Biological Sciences and Academic Health Center (R.S. Harris), the Randy Shaver Cancer Research and Community Fund (R.S. Harris), the Masonic Cancer Center Translational Working Group (T.K. Starr), and the Mezin-Koats Colorectal Cancer Research Fund (T.K. Starr). National Institutes of Health training grants and career development awards provided salary support for R. Levin-Klein (T32HL007062 and F32CA232458) and M.C. Jarvis (T32CA009138 and F31CA243306). R. Levin-Klein is an awardee of the Weizmann Institute of Science National Postdoctoral Award Program for Advancing Women in Science. M.B. Burns was supported in part by a US Department of Defense Breast Cancer Research Program Predoctoral Fellowship (BC101124). R.S. Harris is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.
Disclosures: D.A. Largaespada reported other from NeoClone Biotechnology, Inc., personal fees from BmoGen Biotechnology, Inc., other from Luminary Therapeutics, Inc., other from Re-combinetics, Inc., other from ImmuSoft, Inc., and grants from Genentech, Inc. outside the submitted work. R.S. Harris reported personal fees from ApoGen Biotechnologies outside the submitted work. No other disclosures were reported.
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