Transcriptomic, Proteomic, and Genomic Mutational Fraction Differences Based on HPV Status Observed in Patient-Derived Xenograft Models of Penile Squamous Cell Carcinoma

Abstract

Metastatic penile squamous cell carcinoma (PSCC) has only a 50% response rate to first-line combination chemotherapies and there are currently no targeted-therapy approaches. Therefore, we have an urgent need in advanced-PSCC treatment to find novel therapies. Approximately half of all PSCC cases are positive for high-risk human papillomavirus (HR-HPV). Our objective was to generate HPV-positive (HPV+) and HPV-negative (HPV−) patient-derived xenograft (PDX) models and to determine the biological differences between HPV+ and HPV− disease. We generated four HPV+ and three HPV− PSCC PDX animal models by directly implanting resected patient tumor tissue into immunocompromised mice. PDX tumor tissue was found to be similar to patient tumor tissue (donor tissue) by histology and short tandem repeat fingerprinting. DNA mutations were mostly preserved in PDX tissues and similar APOBEC (apolipoprotein B mRNA editing catalytic polypeptide) mutational fractions in donor tissue and PDX tissues were noted. A higher APOBEC mutational fraction was found in HPV+ versus HPV− PDX tissues (p = 0.044), and significant transcriptomic and proteomic expression differences based on HPV status included p16 (CDKN2A), RRM2, and CDC25C. These models will allow for the direct testing of targeted therapies in PSCC and determine their response in correlation to HPV status.

Keywords

• penile squamous cell carcinoma
• human papillomavirus-positive penile squamous cell carcinoma
• APOBEC mutations
• patient-derived xenograft