Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

Annals of Oncology 29: 563–572, 2018 doi:10.1093/annonc/mdy003 Published online 8 January 2018 REVIEW Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution S. Venkatesan1,2†, R. Rosenthal1†, N. Kanu1, N. McGranahan1, J. Bartek3,4,5, S. A. Quezada1,6, J. Hare7, R. S. Harris8,9,10,11,12*‡ & C. Swanton1,2*‡ 1 CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, London; 2Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK; Danish Cancer Society Research Center, Copenhagen, Denmark; 4Science for Life Laboratory, Stockholm; 5Division of Genome Biology, Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; 6Cancer Immunology Unit, UCL Cancer Institute, London, UK; 7International AIDS Vaccine Initiative (IAVI), New York; 8Masonic Cancer Center, Minneapolis; 9Institute for Molecular Virology, Minneapolis; 10Center for Genome Engineering, Minneapolis; 11 Department of Biochemistry, Molecular Biology and Biophysics; 12Howard Hughes Medical Institute, University of Minnesota, Minneapolis, USA 3 *Correspondence to: Prof. Reuben S. Harris, Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA. Tel: þ1-612-624-0457; Fax: þ1-612-625-2163; E-mail: Prof. Charles Swanton, Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Tel: þ44-0-2072693463; Fax: þ44-0-2072693463; E-mail: † Both authors contributed equally as first authors. ‡ Both authors contributed equally as senior authors. The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer. Key words: APOBEC, immune escape, drug resistance, human immunodeficiency virus, intratumour heterogeneity Introduction Apolipoprotein B mRNA-editing enzyme, catalytic polypeptidelike 3 (APOBEC3; A3) is the name of a seven-membered family of single-stranded DNA cytosine deaminases in humans. Independent approaches including analyses of next-generation sequencing data implicated APOBEC-catalysed DNA damage and mutagenesis in breast cancer [1, 2]. Subsequent studies confirmed and extended the involvement of APOBEC in mutating the cancer genome to at least 16 other cancer types [3–5]. APOBEC signature mutations (C-to-T and C-to-G in TCA and TCT trinucleotide motifs) are the most prevalent in cancer after those attributable to ageing (C-to-T in CG dinucleotide motifs, most likely due to water-mediated deamination of methylcytosine) [4]. Furthermore, the clinical relevance of APOBEC in cancer is underscored by associations with poor patient outcomes and treatment resistance [6, 7], activation of oncogenic drivers [8–10], tumour subclonal diversification [9, 11, 12], and increased prevalence in metastases in comparison with primary tumours [13]. Although involvement of APOBEC mutagenesis in cancer has only recently come to light, these enzymes have been a focus of virology research for over a decade, beginning with the near simultaneous discoveries of APOBEC3G (A3G) as an HIV-1 restriction factor and as a DNA cytosine deaminase [14, 15] (reviewed elsewhere [16, 17]). We envision that many lessons learnt regarding APOBEC within virology will be applicable to oncology. For this reason, we explore the parallels between the role of APOBEC in HIV and cancer mutagenesis. We will especially focus on how APOBEC mutagenesis can promote intratumour heterogeneity, drug resistance, and immune escape. C The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Review The AID/APOBEC superfamily: a diverse set of cytosine deaminase enzymes implicated in cancer APOBEC3 belongs to the AID/APOBEC superfamily, consisting of activation induced deaminase (AID), APOBEC1 (A1), APOBEC2 (A2), APOBEC3A-H (A3A, A3B, A3C, A3D, A3F, A3G, and A3H), and APOBEC4 (A4). AID deaminates cytosines at the immunoglobulin locus, enabling antibody gene diversification via somatic hypermutation, and class switch recombination [18]. A1 was identified originally as an RNA editing enzyme, deaminating apolipoprotein B mRNA at a specific position to create an early stop codon [19], but it also has robust DNA deamination activity [14, 20]. The functions of A2 and A4 are still unclear and these proteins have yet to show enzymatic activity. In general, the A3 family members are considered part of the innate immune system, forming overlapping barriers to virus and transposon replication. Consistent with such a physiological function, A3 genes show profound copy number and amino acid variation in mammals. For instance, most humans have seven A3 genes arranged in tandem, whereas rodents have only one at the same genomic location [21, 22], and each A3 gene in humans as well as several other mammals manifests high levels of amino acid variation due to positive selection [23]. A3G has been studied intensely in the field of virology, as it was recognized early on to deaminate cytosines in cDNA reverse transcription intermediates of retroviruses including HIV-1 [24, 25]. Reverse transcriptase places an adenine opposite to the newly created uracil nucleobase, introducing a viral genomic strand G!A mutation [26]. This inhibits HIV replication by directly rendering the viral genome dysfunctional or by indirectly triggering viral cDNA degradation by subsequent uracil DNA glycosylase activity and endonuclease digestion [26, 27]. A3G can also directly bind to HIV-1 genomic RNA and interfere with viral cDNA synthesis [28]. A3D, A3F, and A3H also contribute to HIV-1 mutagenesis through similar mechanisms, and it is generally accepted that different subsets of A3 family members restrict the replication of different classes of viruses and transposons (reviewed elsewhere [16, 17]). Adding to the complexity of seven A3 family members in humans, different subsets of A3 enzymes are expressed in different tissue types [29, 30]. Together with high levels of DNA sequence similarity (near perfect identity in many regions), determining which of these enzymes is responsible for mut (...truncated)