Abstract A088: Centrosomes take center stage: Comparative analysis of centrosome amplification in African American and European American patients with prostate cancer

Abstract

Abstract Background: Prostatic adenocarcinoma (PCA) in African Americans (AA) is characterized by earlier onset, higher aggressiveness, more frequent metastases, and increased mortality rates compared to those in European Americans (EA). Exome and genome sequencing have revealed that PCA in AAs also exhibits high intratumor heterogeneity (ITH) than their counterparts in EAs. ITH poses challenges to both clinicians and drug developers when identifying low-level clones, predicting tumor evolution, developing clone-specific targeted drugs and evaluating effective, yet non-toxic combinatorial regimens to combat ITH. Amplified centrosomes (an abnormal increase in the number and/or volume of centrosomes) underlie erroneous mitoses and fuel chromosomal instability (CIN), which is a well-recognized driver of ITH. In this study, we evaluated the extent of centrosome amplification in tissue sections from PCA in AA and EA men. Design: We have pioneered a semi-automated pipeline that integrates immunofluorescence confocal microscopy with digital image analysis and yields a quantitative Centrosomal Amplification Score (CAS) for each tumor sample by evaluating severity and frequency of centrosomal aberrations therein. To this end, 115 formalin fixed paraffin embedded PCA tissue sections were firstly immunofluorescently stained for centrosomes followed by imaging and image analysis. Finally, we generated a composite CAS score (CAStotal) for each patient sample by integrating the numerical (CASi) and structural (CASm) aberrations. Results: High BMI (>25) AA PCAs (n=37) exhibited significantly (p=0.04) higher CAStotal than EA (n=41) regardless of Gleason grade. Moreover, on analysis of grade matched PCAs we observed that CASm and CAStotal were significantly higher (p=0.02) in high grade (Gleason score >7) in AA PCAs (n=34) when compared to EA (n=38) PCAs. Regardless of race tumors from men > 54 years exhibited higher CAStotal (p=0.03) (high age group n=86 and low age =29). Conclusion: Our results suggest that AAs exhibit higher degree and severity of CA compared to EAs, which may render PCAs in AAs more sensitive to centrosome targeting/declustering drugs. This study suggests the potential usefulness of CAS in enabling patient stratification into more optimal treatment regimens and provides a novel tool that might help in personalized prostate cancer treatment with an overall goal of eliminating ethnic disparities in prostate cancer outcomes. Citation Format: Karuna Mittal, Guanhao Wei, Jaspreet Kaur, Michelle Dian Reid, Ritu Aneja. Centrosomes take center stage: Comparative analysis of centrosome amplification in African American and European American patients with prostate cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A088.