Abstract Introduction and Objectives: ERG gene fusions leading to ERG overexpression represent a highly prevalent oncogenic alteration (50-70%) in prostate cancer (CaP) patients of Caucasian ethnicity. We and others noted lower ERG frequency in CaP of African Americans (AA) in comparison to Caucasian Americans (CA). There is no study of ERG alterations in CaP patients from India. This study focused on comparative analysis of the frequency of ERG oncoprotein expression in CaP patients with Asian (India, Japan), African (AA) and Caucasian (CA) ethnicity. Materials and Methods: Coded archived FFPE tissue blocks from radical prostatectomy (RP) specimens of 51 patients from the Rajiv Gandhi Cancer Institute (RGCI), New Delhi, India, were analyzed for the presence of ERG oncoprotein by immunohistochemistry (IHC) using a highly specific ERG monoclonal antibody (ERG MAb, 9FY). From Japan, tissue microarray (TMA) derived from surgical specimens of 64 patients (160 cancer spots) with localized CaP was analyzed by the same anti-ERG MAb. A USA cohort of whole mount prostate specimens, minimizing sampling bias and allowing for assessment of ERG in multifocal tumor context, from 91 AA and 91 CA CaP patients (matched for age, Gleason score and pathologic stage) was analyzed by ERG IHC. Results: Of thirty evaluable specimens from India, ERG positive tumors were present in 8 cases (27%). Among 64 patients from Japan, 16 patients (25%) showed at least one positive cancer spot for ERG expression in the TMA. No correlation between ERG status and Gleason score or PSA failure was found. Systematic evaluation of whole mount prostatectomy specimens revealed that the frequency of ERG positive prostate tumors was significantly greater among CA than AA men when assessed in all tumor foci (41.9% vs. 23.9%, p<0.0001) or in index tumors (63.3% vs. 28.6%, p<0.0001). Conclusions: Frequency of ERG oncoprotein expression is much lower in CaP patients with Asian (25-27%) or African (28%) descent than in CaP patients with European descent (63%). This study underscores that typing of prostate tumors for ERG may enhance our understanding of biological differences between ethnic groups. This research in part was supported by the National Cancer Institute R01CA162383 (S. S.) and USU-CPDR funds. Citation Format: Gyorgy Petrovics, Sudhir Rawal, Molly Williams, Philip Rosen, David Pfister, Takahiro Inoue, Osamu Ogawa, Monica Colombo, Yongmei Chen, Denise Young, Albert Dobi, David G. McLeod, Isabell Sesterhenn, Shiv Srivastava. Variation of ERG oncoprotein expression in prostate cancer patients with different ethnicities. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1920. doi:10.1158/1538-7445.AM2013-1920