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Unraveling the Interplay: Microbiome, p16 Expression, High-Risk HPV Infection, and Clinical Outcomes in Penile Cancer Across Diverse Patient Cohorts with Varied Mortality and Incidence Profiles

Award Number: R21CA299578
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Unraveling the Interplay: Microbiome, p16 Expression, High-Risk HPV Infection, and Clinical Outcomes in Penile Cancer Across Diverse Patient Cohorts with Varied Mortality and Incidence Profiles - The incidence and mortality rate of penile squamous cell carcinoma (PSCC) is significantly higher in Puerto Rico compared to the continental United States (US). Puerto Rican men have approximately a three-fold higher incidence rate than non-Hispanic white men in the continental US. Our proposal will compare molecular profiles across 350 primary tumors representing distinct geographic areas to study the spectrum of disease prevalence and discover the possible biological cause of this health disparity. High-risk human papillomavirus genotypes (HR-HPV) are implicated in the carcinogenesis of PSCC through the action of viral E6 and E7 oncoproteins. E6 disrupts the p53 tumor suppressor pathway, while E7 inhibits the retinoblastoma protein (Rb) pathway, leading to increased expression of the p16 protein. Due to the ease of detecting p16 overexpression by immunohistochemistry (IHC), it serves as a marker for HR-HPV infection in PSCC. The World Health Organization recently recommended that p16 status be reported as a “requirement” for PSCC pathology, as it is a recognized biomarker for HR-HPV infection. However, various studies show that the expected concordance between p16 expression and HR-HPV infection may not hold true in high-incidence populations. We suspect that these discrepancies in concordance within such populations could stem from variations in the intratumoral microbiome or DNA methylation patterns. We hypothesize that microbiome profiles and DNA methylation patterns reflect stable reservoirs of biomarkers that indicate how HR-HPV influences the development and progression of PSCC. Our proposal seeks to utilize these markers as prognostic indicators of outcomes in populations with high rates of HR-HPV/p16 discordance. We will evaluate: Aim 1a. HR-HPV subtype using the Roche Cobas system; Aim 1b. p16 expression by IHC; Aim 1c. DNA methylation using reduced representation bisulfite sequencing (RRBS) and Aim 1d. microbiome using 16S rRNA sequencing. We will determine how the overall diversity of the tumor microbiome affects prognosis and how specific microbes correlate with p16 expression, HR-HPV infection, and clinical characteristics such as tumor stage, histological subtype, nodal stage, cancer-specific survival, disease-free survival, and overall survival. Similar correlations will be determined with DNA methylation patterns and specific loci. We are specifically interested in how these correlations differ between geographic areas to identify biological factors associated with PSCC health disparities. Our proposal could significantly change the biomarker used for determining HR-HPV infection in PSCC and could find relevant biomarkers for overall prognosis of PSCC in high incidence regions of the world.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $427,249 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	1	7/30/2026	NEW	$427,249
														Subtotal = $427,249

Grand Total All Awards = $427,249

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Unraveling the Interplay: Microbiome, p16 Expression, High-Risk HPV Infection, and Clinical Outcomes in Penile Cancer Across Diverse Patient Cohorts with Varied Mortality and Incidence Profiles

Award Number: R21CA299578

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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