Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-16802-8
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Funding
- NIH Pathway to Independence Award [CA212154]
- California Breast Cancer Research Program
- University of California Irvine Chao Family Comprehensive Cancer Center Anti Cancer Challenge
- NIH [CA218856, 1S10RR025496-01, 1S10OD010794-01, 1S10OD021718-01]
- MGH Cancer Center startup funds
- MPN Research Foundation Challenge grant
- Cancer Center Support Grant at the University of California, Irvine [P30CA-062203]
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APOBEC3A is a cytidine deaminase driving mutagenesis, DNA replication stress and DNA damage in cancer cells. While the APOBEC3A-induced vulnerability of cancers offers an opportunity for therapy, APOBEC3A protein and mRNA are difficult to quantify in tumors due to their low abundance. Here, we describe a quantitative and sensitive assay to measure the ongoing activity of APOBEC3A in tumors. Using hotspot RNA mutations identified from APOBEC3A-positive tumors and droplet digital PCR, we develop an assay to quantify the RNA-editing activity of APOBEC3A. This assay is superior to APOBEC3A protein- and mRNA-based assays in predicting the activity of APOBEC3A on DNA. Importantly, we demonstrate that the RNA mutation-based APOBEC3A assay is applicable to clinical samples from cancer patients. Our study presents a strategy to follow the dysregulation of APOBEC3A in tumors, providing opportunities to investigate the role of APOBEC3A in tumor evolution and to target the APOBEC3A-induced vulnerability in therapy. The DNA cytosine deaminases APOBEC3A and APOBEC3B have emerged from cancer genomics studies as drivers of mutation in cancers and tumor heterogeneity. Here the authors present a computational approach to identify the RNA mutations specifically driven by APOBEC3A, and developed an RNA mutation-based assay to quantify ongoing APOBEC3A activity in tumor cells.
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