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Transcriptomic, Proteomic, and Genomic Mutational Fraction Differences Based on HPV Status Observed in
Niki M Zacharias1,2, Luis Segarra1,2, Keiko Akagi3
1Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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.
Insights
New penile cancer models reveal biological differences based on HPV status. These patient-derived xenografts will aid in developing targeted therapies for advanced penile squamous cell carcinoma.
Area of Science:
- Oncology
- Virology
- Genetics
Background:
- Metastatic penile squamous cell carcinoma (PSCC) has limited treatment options with a 50% response rate to first-line chemotherapy.
- No targeted therapies are currently available for advanced PSCC.
- High-risk human papillomavirus (HR-HPV) is detected in approximately half of all PSCC cases.
Purpose of the Study:
- To generate patient-derived xenograft (PDX) models for both HPV-positive (HPV+) and HPV-negative (HPV-) PSCC.
- To identify biological distinctions between HPV+ and HPV- PSCC.
- To establish a platform for testing novel targeted therapies in PSCC based on HPV status.
Main Methods:
- Generated four HPV+ and three HPV- PSCC PDX animal models from patient tumor xenografts.
- Validated PDX model fidelity to patient tumors using histology and short tandem repeat fingerprinting.
- Analyzed DNA mutations, APOBEC mutational fractions, and transcriptomic/proteomic expression differences based on HPV status.
Main Results:
- PDX models accurately reflected patient tumor characteristics.
- Similar APOBEC mutational fractions were observed between donor and PDX tissues.
- A significantly higher APOBEC mutational fraction was found in HPV+ versus HPV- PDX tissues (p=0.044).
- Distinct transcriptomic and proteomic differences were identified, including p16 (CDKN2A), RRM2, and CDC25C, correlating with HPV status.
Conclusions:
- Developed reliable HPV+ and HPV- PSCC PDX models.
- Demonstrated distinct biological profiles between HPV+ and HPV- PSCC.
- These models are crucial for preclinical testing of targeted therapies tailored to HPV status in PSCC treatment.
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