Background: APOBECs (apolipoprotein B mRNA-editing catalytic polypeptides) are cytidine deaminases that have been implicated in the host defense against viruses by blocking viral replication. They have also been shown to play a role in genome hypermutation in several human cancers. An APOBEC3 hypermutation signature has been discovered in cervical cancer, which is intimately associated with infection by high-risk human papillomaviruses (HPVs). At the same time, HPV genomes themselves are subject to DNA editing by APOBECs. Similar to cervical cancer, a proportion of penile squamous cell carcinomas (SCCs) is etiologically driven by high-risk HPVs, but very little is known about the role of APOBECs in penile SCC development and progression. Methods: A series of 34 penile SCCs was analyzed for the expression of APOBEC3A protein by immunohistochemistry. HPV genotyping was carried out using a bead-based multiplex hybridization assay preceded by BSGP5+6+ primer-based amplification. Results: We found a frequent reduction of APOBEC3A protein expression in the invasive parts of the majority of HPV-negative penile SCCs. In contrast, the majority of HPV-positive penile SCCs retained APOBEC3A expression during malignant progression. Conclusion: Our results suggest that APOBEC3A expression is downregulated during progression towards invasiveness in HPV-negative penile SCC, but maintained in HPV-positive penile SCC. How high-risk HPV-infected tumor cells tolerate high APOBEC3A, which appears to exert tumor suppressive functions in HPV-negative penile SCCs, remains to be elucidated.

Henderson S, Fenton T: APOBEC3 genes: retroviral restriction factors to cancer drivers. Trends Mol Med 2015;21:274-284.
Swanton C, et al: APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov 2015;5:704-712.
Henderson S, et al: APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep 2014;7:1833-1841.
Lackey L, et al: Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination. Cell Cycle 2013;12:762-772.
Narvaiza I, Landry S, Weitzman MD: APOBEC3 proteins and genomic stability: the high cost of a good defense. Cell Cycle 2012;11:33-38.
Schumann GG: APOBEC3 proteins: major players in intracellular defence against LINE-1-mediated retrotransposition. Biochem Soc Trans 2007;35(pt 3):637-642.
Green AM, et al: APOBEC3A damages the cellular genome during DNA replication. Cell Cycle 2016;15:998-1008.
Landry S, et al: APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep 2011;12:444-450.
Hoopes JI, et al: APOBEC3A and APOBEC3B preferentially deaminate the lagging strand template during DNA replication. Cell Rep 2016;14:1273-1282.
Roberts SA, et al: An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 2013;45:970-976.
Alexandrov LB, et al: Signatures of mutational processes in human cancer. Nature 2013;500:415-421.
Nik-Zainal S, et al: Mutational processes molding the genomes of 21 breast cancers. Cell 2012;149:979-993.
Vartanian JP, et al: Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 2008;320:230-233.
Kondo S, et al: APOBEC3A associates with human papillomavirus genome integration in oropharyngeal cancers. Oncogene 2017;36:1687-1697.
Warren CJ, et al: APOBEC3A functions as a restriction factor of human papillomavirus. J Virol 2015;89:688-702.
Hakenberg OW, et al: EAU guidelines on penile cancer: 2014 update. Eur Urol 2015;67:142-150.
Prigge E-S, von Knebel Doeberitz M, Reuschenbach M: Clinical relevance and implications of HPV-induced neoplasia in different anatomical locations. Mut Res Rev Mutat Res 2017;772:51-66.
Feber A, et al: CSN1 somatic mutations in penile squamous cell carcinoma. Cancer Res 2016;76:4720-4727.
Prigge ES, et al: p16INK4a/Ki-67 co-expression specifically identifies transformed cells in the head and neck region. Int J Cancer 2015;136:1589-1599.
Reuschenbach M, et al: High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients. Br J Cancer 2011;104:1334-1341.
Chan K, et al: An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet 2015;47:1067-1072.
Lau SK, Chu PG, Weiss LM: CD163: a specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 2004;122:794-801.
Chen S, et al: APOBEC3A possesses anticancer and antiviral effects by differential inhibition of HPV E6 and E7 expression on cervical cancer. Int J Clin Exp Med 2015;8:10548-10557.
Land AM, et al: Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and nongenotoxic. J Biol Chem 2013;288:17253-17260.
Lont AP, et al: Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006;119:1078-1081.
Djajadiningrat RS, et al: Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol 2015;193:526-531.
Chang LC, et al: APOBEC3G exerts tumor suppressive effects in human hepatocellular carcinoma. Anticancer Drugs 2014;25:456-461.
McLaughlin-Drubin ME, Meyers J, Munger K: Cancer associated human papillomaviruses. Curr Opin Virol 2012;2:459-466.
Spardy N, et al: Human papillomavirus 16 E7 oncoprotein attenuates DNA damage checkpoint control by increasing the proteolytic turnover of claspin. Cancer Res 2009;69:7022-7029.
Hoskins EE, et al: The fanconi anemia pathway limits human papillomavirus replication. J Virol 2012;86:8131-8138.
Aynaud MM, et al: Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A. J Biol Chem 2012;287:39182-39192.
Chinnadurai G: CtIP, a candidate tumor susceptibility gene is a team player with luminaries. Biochim Biophys Acta 2006;1765:67-73.
Narvaiza I, et al: Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathog 2009;5: e1000439.
Iwatani Y, et al: Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G. Nucleic Acids Res 2007;35:7096-7108.
Horn AV, et al: Human LINE-1 restriction by APOBEC3C is deaminase independent and mediated by an ORF1p interaction that affects LINE reverse transcriptase activity. Nucleic Acids Res 2014;42:396-416.
Kanu N, et al: DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer. Genome Biol 2016;17:185.
Spardy N, et al: HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies. Cancer Res 2008;68:9954-9963.
Wang Z, et al: APOBEC3 deaminases induce hypermutation in human papillomavirus 16 DNA upon beta interferon stimulation. J Virol 2014;88:1308-1317.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.