Abstract 1230: Association of common germline variants with TMPRSS2-ERG gene fusion status in prostate cancer

Abstract

Abstract Introduction and Objectives: Oncogenic activation of ERG resulting from prevalent gene fusions (predominantly as TMPRSS2-ERG) is a key driver event in prostate cancer (CaP) pathogenesis. Our laboratory and others have recently reported that major cancer driver genes, including ERG, show significant racial/ethnic differences in CaP. It is present in two thirds of CaP patients of European Ancestry including Caucasian Americans (CA) but is present at lower frequencies in African Americans (AA), Africans and Asians. Racial differences of CaP associated SNPs have also been extensively described. However, there is limited data on germline association with ERG fusion status. The goal of this study is to identify germline molecular determinants associating with ERG status of CaP. Methods: Blood derived genomic DNA samples were prepared from 270 AA men and 130 CA men treated by radical prostatectomy. ERG status was determined by immuno-histochemistry (IHC) for ERG protein expression. SNP genotyping was performed on the Illumina Golden Gate platform using Infinium Oncoarray SNP chip. Data analysis approaches included association analyses based on EMMAX and imputation analysis by IMPUTE2. SNP genotyping was performed using droplet digital polymerase chain reaction (ddPCR) approach Results: SNP genotyping analysis was performed in 321 patients with 478,299 SNPs. We identified SNPs associated with ERG status using EMMAX analysis. The SNPs most significantly (p <10-5) associated with ERG fusion status included rs6698333, an intron variant of Kruppel-like factor 17 (KLF17) and two SNPs (rs1889877, rs3798999) in the intron of adhesion G protein-coupled receptor B3 (ADGRB3). 4 SNPs (rs10215144, rs3818136, rs9380660 and rs1792695) were found to be significantly (p <10-5) associated with ERG positive phenotype under any tumor foci positive for the fusion. Fine-mapping of SNPs by genotype imputation analysis (IMPUTE2) using the 1000 Genomes reference dataset, found rs34349373 and rs2055272 to be significantly associated (p <10-7). The 2 variants were found to be in strong linkage disequilibrium (LD) in both CA and AA populations with r2 of 1.0 and 0.91 respectively. Imputed SNP rs2055272 was further experimentally evaluated by Taqman based ddPCR SNP genotyping approach. Concordance between Taqman genotypes and imputed genotypes was found to be 98.04%. Association analysis of the SNPs with clinico-pathological features of CaP and functional annotation of the significant SNPs by in silico eQTL based analysis are being performed. Conclusions: This study identified SNPs associated with ERG status of CaP, a major driver oncogene in CaP. Although the biological significance as it relates to ERG status of CaP still needs to be determined, these SNPs, with independent validation, may help as markers in stratifying patients early (even before CaP is detected) for targeted prevention and treatment options. Citation Format: Indu Kohaar, Yongmei Chen, Lakshmi Ravindranath, Denise Young, Amina Ali, Qiyuan Li, Albert Dobi, Inger L. Rosner, Isabell Sesterhenn, Jennifer Cullen, Matthew Freedman, Shiv Srivastava, Gyorgy Petrovics. Association of common germline variants with TMPRSS2-ERG gene fusion status in prostate cancer [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 1230.