title: APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Francis Crick Institute, London, United Kingdom. UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London, United Kingdom. charles.swanton@crick.ac.uk rsh@umn.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.affiliation: The Francis Crick Institute, London, United Kingdom. Centre for Mathematics & Physics in the Life Sciences & Experimental Biology (CoMPLEX), University College London, London, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Starrett
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. charles.swanton@crick.ac.uk rsh@umn.edu.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000071478:APOBEC Deaminases; D003564:Cytidine Deaminase; D003596:Cytosine / Q000378:metabolism; D043525:Cytosine Deaminase / Q000235:genetics*; D003641:Deamination; D019143:Evolution, Molecular; D018740:Genetic Heterogeneity; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D003596:Cytosine; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase