Abstract A018: Distinct genomic alterations in prostate cancer of African American men

Abstract

Abstract Background: In recent years remarkable ethnic/racial differences in the frequency of prostate cancer (CaP) driver gene alterations have emerged. Along the lines of ethnic differences in CaP genomes, oncogenic activation of ERG proto-oncogene and deletion of the PTEN tumor suppressor gene are most widely studied. These findings underscore distinct biology of prostate cancer in different ethnicities and races. We have reported the cumulative analyses of 435 patients (whole genome sequencing (WGS): 14, FISH evaluations: 101, SNP array: 320) comparing CaP genomes of African American (AA) and Caucasian American (CA) patients. An AA CaP genome-associated deletion was identified and mapped to the Limbic System-Associated Membrane Protein (LSAMP) gene locus. Further examination of the data indicated the AA CaP-genome associated deletion of the Chromodomain Helicase DNA Binding Protein 1(CHD1) gene. The goal of the current study is the comparative assessment of frequencies and prognostic associations of CaP genome alterations in the context of racial/ethnic differences. Methods: A prostate tumor tissue microarray (TMA) of benign and tumor foci (500+ cores) was generated by sampling 2-3 cores representing the range of cell morphology in matched cohort of 42 AA and 59 CA patients with up to 20 years of follow-up. Comparative evaluation of frequencies and prognostic associations of ERG oncoprotein by immunohistochemistry and the deletion of LSAMP, CHD1, and PTEN genes by FISH was performed. ERG frequencies were further assessed in index tumors of Chinese CaPs (N=100) and were compared to ERG frequencies in index tumors of patients from the United States equal-access military health-care system (N=336 AA and N=594 CA). Results: Higher frequencies of recurrent deletions of CHD1 (29% AA vs. 10% CA p=0.017) and LSAMP (26% AA vs. 7% CA, p=0.006) were identified in AA CaP compared to CA CaPs. These deletions were associated with significantly higher risk of rapid biochemical recurrence. In contrast, PTEN deletions (15% AA vs. 63% CA) and the frequency of ERG positive CaPs (26% AA vs. 64% CA) were more frequent among CA CaPs. Comparative evaluation of ERG frequencies in CaPs (N=1,292) underscores highest ERG frequency among CA patients (49.3%) followed by AA (23.2%) and Chinese (22%) men. Conclusions: In light of distinct biology of CaPs in ethnically/racially diverse CaP patient populations, there is a need for developing broadly applicable diagnostic, prognostic marker panels and therapeutic approaches. Higher frequency of CHD1 deletion in CaPs of AA patients may provide new therapeutic opportunities due to the sensitivity of CHD1 deletion harboring tumors to PARP inhibitors and platinum agents. Acknowledgments: This research was supported by the CPDR-USU program HU0001-10-2-0002, the National Cancer Institute R01CA162383 grant, the EDRN/NCI ACN12011-001-0 grant, the Snyder Medical Foundation, the Otto Mønsteds Foundation, the Mazzone Foundation, the Breast Cancer Research Foundation, the Novo Nordisk Foundation, and grants by MTA-TKI643/2012, KTIA_NAP_13-2014-0021. Citation Format: Albert Dobi, Gyorgy Petrovics, Hua Li, Denise Young, Shyh-Han Tan, Yongmei Chen, Qingyu Xiao, Yidi Sun, Hong Li, Yixue Li, Yuan Ji, Jun Hou, Wendy Wang, Jacob Kagan, Guo-Ping Zhao, Sudhir Srivastava, Reinhard Ebner, Inger L. Rosner, Jennifer Cullen, Matthew Freedman, Isabell Sesterhenn, Zoltan Szallasi, Shiv Srivastava. Distinct genomic alterations in prostate cancer of African American men [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A018.