SUMMARY Prostate cancer (PCa) is the second most common cancer in men in the United States. The absolute number of men with PCa is projected to increase as a result of the ageing baby boomer population. However, the lack of reliable biomarkers for PCa screening has led to decreased early detection, particularly for African American (AA) men who have the highest PCa morbidity, metastatic risk and mortality rates than any other racial or ethnic group in the US. When cancer is suspected, patients must undergo multiple needle core biopsies because of the multifocal nature of PCa. Nonetheless, up to 34% of biopsied men are told they are cancer-free when they are not, because the biopsies missed the cancer foci. Hence, it is critical to better define the cellular and molecular features indicative of PCa development and risk for aggressive disease in benign biopsies of PCa patients to improve diagnosis and screening. In this grant, we are proposing to explore a variation on the concept of field effect in PCa, postulating that histopathologically benign looking prostate core biopsies may in fact feature alterations indicative of PCa and of PCa aggressiveness present in the same patient at another prostatic site, using age- and race-matched (AA and Caucasian Americans (CA)) sets of samples (benign and cancer-bearing biopsies for each patient). Prostate-resident mast cells (MC) aggregate in stromal, peritumoral and/or intratumoral areas but their clinical relevance remains controversial. Our preliminary data suggests the usefulness of establishing MC profiles in benign prostatic tissues of PCa patients. The objectives of this application are: to investigate MC functional profiles in benign human prostate tissues as predictors of PCa aggressiveness and candidate functional biomarkers of PCa race disparity; to define and validate a molecular signature indicative of PCa and PCa aggressiveness present in benign human prostate biopsies and test its predictive value for PCa disparity and association to MC; and apply our new screening modalities in clinics, contingent upon successful validation studies. We anticipate that our approach may improve diagnosis and screening for high-risk PCa and position MC as potential drivers of PCa disparity.

NARRATIVE Definitive diagnosis of prostate cancer (PCa) relies on the collection of multiple core needle biopsies and their histopathological analysis but the multifocal nature of PCa makes cancer foci easy to miss, leading to a high rate of false negative results. Elevated PCa incidence rates, aggressiveness and mortality are more substantial in African American than in Caucasian American men. Our studies seek to identify and validate specific functional and phenotypic profiles of mast cells and molecular signatures present in benign biospies collected from PCa patients to improve PCa diagnosis, also having implications in PCa race disparity.