Prostate cancer (PCa) is a heterogeneous disease and the diverse clinical outcomes may be associated with hitherto unidentified tumor molecular heterogeneity. In the era of precision medicine, new approaches to identify distinct molecular subsets of tumors may lead to the development of targeted treatment options. Given the disparity in the disease progression between African American (AA) and Caucasian American (CA) patients, understanding the existence of distinct molecular subtypes between the two racial groups may facilitate effective cancer management. Therefore, we carried out a comprehensive molecular analysis using prostate cancer-specific molecular markers, including ERG, ETV1, ETV4, ETV4, ETV5 and SPINK1, to study tumor molecular heterogeneity in a large cohort of AA and CA PCa patients. A total of 1,117 PCa cases comprising 575 (52%) CA and 453 (41%) AA patients were included in this study. Dual IHC for ERG/SPINK1 and RNA ISH for ETV1, ETV4 and ETV5 were carried out on whole mount prostatectomy specimens. Incidence of markers in each tumor foci, difference between the two racial groups, and the association of the markers with the clinical and pathologic findings in each racial group were analyzed. Independent clonal origin of tumor foci in patients with multifocal disease were observed with the presence of dual and triple marker positivity in dominant and/or secondary tumor foci. ERG was more frequently overexpressed among CA patients (P=0.0000) while SPINK1 was more prevalent among AA patients (P=0.0000). The incidence of dual marker positive cases for ERG+/SPINK1+ and SPINK1+/ETV1+ were more prevalent among AA patients than CA patients (P=0.0124 and P=0.0417, respectively). In both CA and AA patients, ERG overexpression is associated with young men age lower than 50 and a positive perineural invasion,(CA; P=0.0037 and P=0.0199, respectively; AA; P= 0.0338 and P=0.0309, respectively). Among CA patients, ERG overexpression also associated with a lower Gleason grade group (group 1 and 2, P=0.0483). SPINK1 overexpression associated with grade group lower than 5 and a negative family history among AA patients (P=0.0003 and P=0.0063). In CA patients, SPINK1 overexpression associated with grade group higher than 1, pT3 stage and tumor volume larger than 10% (P= 0.0036, P=0.0426 and P=0.0377, respectively). ETV1 overexpression is associated with positive family history (P=0.0043) and ETV4 overexpression associated with a tumor volume of 1-10% (P=0.0385) in CA patients. In AA patients, ETV4 expression associated with an age higher than 70 (P=0.0212). ERG/SPINK1 overexpression associated with grade group 2, tumor volume of 10-20%, and an age lower than 70 among CA patients (P=0.0013, P=0.0316, and P=0.0191, respectively). AA patients, on the other hand, showed an association between ERG/SPINK1 and age group lower than 40 (P=0.0092). We will discuss the details on the identification of new molecular subsets of PCa with clonal molecular heterogeneity in racial disparity perspective.

Citation Format: Shannon Carskadon, Mireya Diaz-Insua, Nilesh Gupta, Sean Williamson, Craig Rogers, James Peabody, Mani Menon, Nallasivam Palanisamy. Comprehensive molecular mapping of prostate cancer- Approaching health disparities in molecular tumor heterogeneity perspective [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A113.