Abstract
APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations in over 50% of cancers. APOBEC mutagenesis has been linked to tumor heterogeneity, persistent cell evolution, and therapy responses. While emerging evidence supports the impact of APOBEC mutagenesis on cancer progression, the understanding of its contribution to cancer susceptibility and malignant transformation is limited. We examine the existing evidence for the role of APOBEC mutagenesis in carcinogenesis on the basis of the reported associations between germline polymorphisms in genes encoding APOBEC enzymes and cancer risk, insights into APOBEC activities from sequencing efforts of both malignant and non-malignant human tissues, and in vivo studies. We discuss key knowledge gaps and highlight possible ways to gain a deeper understanding of the contribution of APOBEC mutagenesis to cancer development.