Abstract 4649: Development of an ethnicity informed gene expression panel with potential to improve prostate cancer diagnosis
Authors: Indu Kohaar, Lakshmi Ravindranath, Sreedatta Banerjee, Yongmei Chen, Amina Ali, Yingjie Song, Jacob Kagan, Sudhir Srivastava, Albert Dobi, David McLeod, Inger L. Rosner, Shiv Srivastava, Gyorgy Petrovics
Journal: Cancer Research (2017)

Abstract Introduction and Objectives: Prostate cancer (CaP) affects 1 in 7 men throughout their life time. One of the major risk factors for the development of CaP is race/ethnicity. African American (AA) men have significantly higher incidence and mortality from CaP compared to Caucasian American (CA) men. Emerging data including ours have described significantly lower frequencies of alterations in the common CaP driver genes (ERG and PTEN) in AA men as compared to CA men. We have also noted that genes commonly overexpressed in CaP (ERG, AMACR and PCA3), and currently used as diagnostic markers, exhibit much lower frequency and more heterogeneity in AA men. The goal of this study was to define a broader CaP marker panel that is overexpressed equally well in AA and CA CaP. Methods: Three platforms (RNASeq, NanoString and QRT-PCR) were used for evaluation of CaP associated gene expression in CA and AA patients (N=144). Candidate genes with robust tumor overexpression (over 4-fold) in CaP in comparison of paired normal and tumor specimens from AA and CA patients were selected from the Nanostring and RNASeq data for validation by QRT-PCR (TaqMan) in laser microdissected (LCM) tumor and benign cells of frozen tissue sections (50 CA and 35 AA). An assay protocol (gene specific pooled RT and pre-amplification followed by TaqMan PCR) was set up for the noninvasive early detection of candidate genes in regular patient urine (non-DRE) using RNA derived from urinary exosomes. Results: As expected tumor transcriptomes of CA patients revealed consistently elevated expression of PCA3 and AMACR genes. However, these genes had variable overexpression in AA cohort. The top genes that were similarly over expressed in tumors of AA and CA patients were validated by real time QRT-PCR (TaqMan) analysis in LCM dissected tumor and normal epithelial cells (N=85). At least one gene of a six gene signature (DLX1, HOXC4, NKX2-3, COL10A1, HOXC6 and PSGR) was overexpressed in tumor cells of all AA and CA cases, providing a consistent ethnicity informed tumor expression signature, which was further validated in silico in TCGA RNASeq data. Urinary exosome based assay was developed and optimized for PSGR, DLX1, HOXC4, NKX2-3, as well as PCA3 and ERG. Sensitivity and specificity with optimal cutoff for the urine marker panel was 71% and 61% respectively (N=40). Evaluation of the assay performance in CA and AA patients in a prospective independent cohort of 100 patients addressing race specific performance is in progress. Conclusions: A CaP tissue based gene expression marker panel has been defined with potential diagnostic utility for both CA and AA men in the context of urinary exosomes. Citation Format: Indu Kohaar, Lakshmi Ravindranath, Sreedatta Banerjee, Yongmei Chen, Amina Ali, Yingjie Song, Jacob Kagan, Sudhir Srivastava, Albert Dobi, David McLeod, Inger L. Rosner, Shiv Srivastava, Gyorgy Petrovics. Development of an ethnicity informed gene expression panel with potential to improve prostate cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4649. doi:10.1158/1538-7445.AM2017-4649