Evaluation of Prostate Tumor Molecular Heterogeneity Using Whole Mount Radical Prostatectomy by Dual Immunohistochemistry and Dual RNA in SITU Hybridization
Arachchige PD, Carskadon S, Dhamdhere G, Diaz-Insua M, Stricker H, Rogers C, Peabody J, Menon M, Williamson S, Gupta N, and Palanisamy N. Evaluation of Prostate Tumor Molecular Heterogeneity Using Whole Mount Radical Prostatectomy by Dual Immunohistochemistry and Dual RNA in SITU Hybridization. Cancer Res 2019; 79(13).
Prostate cancer (PCa) remains the second most common cancer among American men. Morphological heterogeneity in prostate cancer is well recognized, however, recent investigations revealed molecular heterogeneity with the existence of unique molecular aberrations among patient sub groups. Molecular heterogeneity may be associated with distinct routes of disease progression, thereby, enabling the use of molecular profiling to facilitate targeted therapy. Importantly, African Americans (AA) are known to develop more aggressive forms of PCa compared to Caucasian Americans (CA). Therefore, the identification of distinct molecular profiles between the two groups may lead to more precise treatment options for PCa patients. Given that a comprehensive molecular mapping, encompassing both AA and CA patients is lacking, we carried out an extensive profiling of multiple molecular markers in a large cohort of AA and CA PCa patients. Whole-mounted post-prostatectomy tissues were obtained from 1117 patients who underwent radical prostatectomy surgery at our institute. The selected cases included 575 (52%) CA and 453 (41%) AA patients. The presence of ERG, SPINK1, ETV1, ETV4 and ETV5 was evaluated using dual IHC and dual RNA ISH. The racial disparity in the molecular marker incidence was analyzed. The incidence of ERG was observed in 52.0% (436/839) of cases while SPINK1 incidence occurred in 45.1% (378/838) cases. The incidence of other ERG family rearrangements, ETV1, ETV4 and ETV5 was low with 9.9% (78/791), 3.8 % (28/733) and 0.6% (2/350) cases respectively. A total of 260 cases showed the incidence of multiple markers on a single prostate. Of these, ERG+/SPINK1 + was prominent with an incidence of 18% (151/838), followed by ERG+/ETV1 + which occurred in 5.2% cases (41/790). In most cases, multiple marker incidence was detected in separate foci, supporting the independent clonal origin of tumor foci in patients with multi focal disease. In a subset of cases, the co-occurrence of ERG and SPINK1 in the same foci was observed, suggesting intra tumor heterogeneity, however, in majority of the cases mutually exclusive pattern of expression was observed, indicating the presence of unique driver molecular aberrations in each tumor foci. Statistical analysis revealed significant incidence of ERG+ in CA (P=0.00) and SPINK1 in AA patients (P=0.00). Additionally, the incidence of ERG/SPINK1 and SPINK1/ETV1 were more frequent among AA patients compared to CA patients (P=0.0124 and P=0.0417). In conclusion, our study highlights the existence of significant molecular heterogeneity among PCa patients in a racially disparate perspective. Consequently, a thorough understanding of the clinical association between distinct molecular sub groups and disease progression in each racial group will significantly aid the treatment efforts in combatting PCa disease.