Racial/ethnic differences in prostate cancer genomic alterations

Background: Distinct biology of prostate cancer (CaP) among men of different races and ethnicities have been recently highlighted. Along these lines higher frequencies of the most common CaP gene alterations, ERG proto-oncogene activation and deletion of the PTEN tumor suppressor, have been reported among Caucasian Americans (CA) when compared to other racial/ethnic groups. We have reported the cumulative analyses of CaPs from 435 patients (whole genome sequencing (WGS), FISH evaluations and SNP arrays) that highlighted the recurrent deletion and disease progression association of the Limbic System-Associated Membrane Protein (LSAMP) in CaP genomes of African American (AA) men. Further examination of these data indicated the AA CaP genome associated recurrent deletion of the Chromodomain Helicase DNA Binding Protein 1(CHD1) gene. Methods: Combined evaluation of frequencies and prognostic associations of ERG oncoprotein by immunohistochemistry and deletions of LSAMP, CHD1 and PTEN genes by FISH were performed using a multi-core TMA (42 AA and 59 CA patients) with longitudinal follow up data (median 16 years). CaP and matched blood genomic DNA samples (N=60) from AA patients were analyzed by WGS. ERG frequencies were further evaluated in index tumors of Chinese CaPs (N=100) and were compared to ERG frequencies in index tumors of AA (N=336) and CA (N=594) patients. Results: Frequent deletions of CHD1 (29% AA vs. 10% CA p=0.017) and LSAMP (26% AA vs. 7% CA, p=0.006) were found in AA CaPs by FISH assay. Both of these deletions were associated with rapid disease progression. Evaluation of CaPs by WGS further highlighted the recurrent deletion of CHD1 among AA men. Comparative evaluation of ERG (AA, N=336; CA, N=594, and Asian N=100) underscored highest ERG frequencies 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. Recurrent CHD1 deletion in CaPs of AA patients may provide new therapeutic opportunities in light of recent reports suggesting that CaP patients harboring CHD1 deletion may benefit from PARP inhibitor or platinum agents therapies. Funding: This study was supported by CPDR, USUHS, HU0001-10-2-0002 to I.L.R., the NCI/EDRN IAA ACN12011-001-0 to S.S. and by the NCI R01CA162383 to S.S. Citation Format: Albert Dobi, Gyorgy Petrovics, Shyh-Han Tan, Hua Li, Denise Young, Cara Schafer, Jesse Fox, Kevin Babcock, Heng-Cheng Hu, Gauthaman Sukumar, Yingjie Song, Lakshmi Ravindranath, Yongmei Chen, Joseph Cheng, Reinhard Ebner, Qingyu Xiao, Yidi Sun, Yixue Li, Yuan Ji, Jun Hou, Wendy Wang, Guo-Ping Zhao, Jacob Kagan, Sudhir Srivastava, Joel T. Moncur, Clifton L. Dalgard, Matthew Wilkerson, Inger L. Rosner, Jennifer Cullen, Matthew Freedman, Zoltan Szallasi, Isabell A. Sesterhenn, Shiv Srivastava. Racial/ethnic differences in prostate cancer genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5352.