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. 2015 Jun 1;21(11):2624-34.
doi: 10.1158/1078-0432.CCR-14-2667. Epub 2015 Feb 27.

Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy

Daniel N Cohen  1 , Steven K Lawson  2 , Aaron C Shaver  2 , Liping Du  3 , Harrison P Nguyen  4 , Qin He  4 , Douglas B Johnson  3 , Wilfred A Lumbang  5 , Brent R Moody  6 , James L Prescott  7 , Pranil K Chandra  7 , Alan S Boyd  8 , Jeffrey P Zwerner  9 , Jason B Robbins  10 , Stephen K Tyring  4 , Peter L Rady  4 , James D Chappell  2 , Yu Shyr  3 , Jeffrey R Infante  11 , Jeffrey A Sosman  3
Affiliations

Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy

Daniel N Cohen et al. Clin Cancer Res. .

Abstract

Purpose: BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC.

Experimental design: Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology.

Results: Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected.

Conclusions: We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general.

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Figures

Figure 1
Figure 1. Sun exposed sites most frequently harbor BRAFi-cSCC
Distribution and histopathology of all adverse cutaneous squamous cell carcinoma (cSCC) lesions from male (blue, left) and female (rose, right) patients with advanced melanoma treated with BRAF-inhibition (BRAFi). Conventional-cSCC (circles), well-differentiated keratoacanthomatous–type SCC (squares) and conv.-cSCC or cSCC-KA with wart-like features (cSCC-WF, stars).
Figure 2
Figure 2. Adverse cutaneous neoplasia during BRAF-inhibition
Histopathologic subtypes of squamoproliferative lesions include verruca (A) with papillomatosis, hyperkeratosis and hypogranulosis; actinic keratosis (not shown) with keratinocyte atypia without full thickness involvement or invasion; conventional (conv.) cutaneous squamous cell carcinoma (cSCC, B, atypical keratinocytes, inset E) with invasion of dermis; well differentiated keratoacanthomatous-type cSCC (cSCC-KA, F); and cSCC with wart-like features (cSCC-WF, C; atypical keratinocytes inset D). H&E stained sections, composite 4x orig. obj. mag. Insets (D, E) 20x orig. obj. mag.
Figure 3
Figure 3. BRAF-inhibition induced cutaneous squamous cell carcinoma latency by UV-radiation exposure and histopathology
Time course of lesion development is multifactorial and statistically related to ultraviolet radiation exposure and is associated with characteristic histopathology. Box-whisker plot with median (black horizontal line), 25th and 75th percentile (box) and min and max (whiskers). All cSCC samples for vemurafenib treated patients are shown (circles) by histomorphologic subtype and presence (+) or absence (–) of ultraviolet (UV) radiation exposure. *Significant 14.0 week decrease in latency in conventional type cSCC with UV radiation exposure (p-value = 0.016). **Significant 11.6 week decrease in latency in cSCC-WF ver. conv.-cSCC when matched for gender and UV-exposure in a multivariate model (p-value = 0.030).
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