The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions

Abstract

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.

Occurrence of newly discovered human polyomaviruses in skin of liver transplant recipients and their relation with squamous cell carcinoma in situ and actinic keratosis – a single‐center cohort study

“…All these HPyVs in premalignant/benign skin occurred in low copy numbers, unlike the same viruses in their associated skin diseases . This is concordant with previous studies on MCPyV, HPyV6, HPyV7, TSPyV, and HPyV9 in SCC precursors and SCC, pointing to virus latency or shedding, rather than activation. Of the additional five new HPyVs studied here, only LIPyV was encountered in skin.…”

Prevalence of DNA of fourteen human polyomaviruses determined in blood donors

“…Each sample was analyzed for the presence of HPyV genomic DNA with the help of three real‐time multiplex quantitative PCR (qPCR) procedures (Multiplex 1, 2, and 3), developed to detect 14 PyVs (Table ). The PCR procedures for BKPyV, HPyV6, HPyV7, TSPyV, and HPyV9 were previously designed and described . The PCR procedures for JCPyV, WUPyV, and MCPyV were developed by other research groups .…”

A Systematic Review and Meta-Analysis: EvaluatiA Systematic Review and Meta-Analysis: Evaluation of the β-Human Papillomavirus in Immunosuppressed Individuals with Cutaneous Squamous Cell Carcinoma with Cutaneous Squamous Cell Carcinoma

“…Table 1 is illustrated the features of eleven studies included in the meta-analysis published from 1989 to 2018. Four studies were presented from United Kingdom [16][17][18][19], two from the Netherlands [20,21], one from Scotland [22], one from the United States of America [23], one from Ireland [24], one from Germany [25] and one was a multicenter study (Queensland, Australia, and Italy) [26]. Six studies were uncontrolled [16,19,[22][23][24][25], two were case-control [20,26] and three were cohort [17,18,21] studies.…”