The role of human papillomaviruses and polyomaviruses in BRAF-inhibitor induced cutaneous squamous cell carcinoma and benign squamoproliferative lesions

Purdie, K. J. et al. (2018) The role of human papillomaviruses and polyomaviruses in BRAF-inhibitor induced cutaneous squamous cell carcinoma and benign squamoproliferative lesions. Frontiers in Microbiology, 9, 1806. (doi: 10.3389/fmicb.2018.01806) (PMID:30154763) (PMCID:PMC6102365)

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Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC. Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays. Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012–2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden. Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK and the British Skin Foundation. IL is funded by the European Research Council and a strategic grant from the Welcome Trust.
Glasgow Author(s) Enlighten ID:Inman, Professor Gareth
Authors: Purdie, K. J., Proby, C. M., Rizvi, H., Griffin, H., Doorbar, J., Sommerlad, M., Feltkamp, M. C., Meijden, E. V. d., Inman, G. J., South, A. P., Leigh, I. M., and Harwood, C. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Frontiers in Microbiology
Publisher:Frontiers Media
ISSN (Online):1664-302X
Copyright Holders:Copyright © 2018 Purdie, Proby, Rizvi, Griffin, Doorbar, Sommerlad, Feltkamp, Van Der Meijden, Iman, South Leigh and Harwood
First Published:First published in Frontiers in Microbiology 9:1806
Publisher Policy:Reproduced under a Creative Commons License

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