Deep sequencing technologies are revealing the complexities of cancer evolution, casting light on mutational processes fueling tumor adaptation, immune escape, and treatment resistance. Understanding mechanisms driving cancer diversity is a critical step toward developing strategies to attenuate tumor evolution and adaptation. One emerging mechanism fueling tumor diversity and subclonal evolution is genomic DNA cytosine deamination catalyzed by APOBEC3B and at least one other APOBEC family member. Deregulation of APOBEC3 enzymes causes a general mutator phenotype that manifests as diverse and heterogeneous tumor subclones. Here, we summarize knowledge of the APOBEC DNA deaminase family in cancer, and their role as driving forces for intratumor heterogeneity and a therapeutic target to limit tumor adaptation.

Significance: APOBEC mutational signatures may be enriched in tumor subclones, suggesting APOBEC cytosine deaminases fuel subclonal expansions and intratumor heterogeneity. APOBEC family members might represent a new class of drug target aimed at limiting tumor evolution, adaptation, and drug resistance. Cancer Discov; 5(7); 704–12. ©2015 AACR.