期刊
NATURE GENETICS
卷 54, 期 11, 页码 1599-1608出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01196-8
关键词
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资金
- European Molecular Biology Organization Long-Term Fellowship [ALTF 760-2019]
- National Cancer Institute (NCI) [CA270102]
- NCI [CA270102, K08CA21299, CA212290, CA008748, CA261183]
- Pew Charitable Trusts
- V Foundation
- Starr Cancer Consortium
- Emerald Foundation
- Department of Defense [CA2000867]
- American Cancer Society
- Cancer Research Foundation
- Children's Discovery Institute
- National Institutes of Health [CA181259, CA185799]
- Geoffrey Beene at the MSKCC
- Ludwig Center at the MSKCC
This translated passage discusses the characteristics of APOBEC3 enzyme mutations associated with cancer, the presence of APOBEC3 mutations in cancer cell lineages, and the potential benefits of inhibiting APOBEC3 mutations in cancer treatment.
Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and ARE acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer. This Perspective addresses next steps to investigate the predictions that inhibition of APOBEC3-mediated mutagenesis may limit tumor heterogeneity, metastasis and drug resistance in a broad range of cancer types by highlighting gaps in our understanding of APOBEC3 biology in cancer and in healthy tissues and strategies to address them.
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