Abstract A013: Prostate cancer gene expression panel to address racial differences of molecular alterations in prostate cancer
Authors: Indu Kohaar, Sreedatta Banerjee, Lakshmi Ravindranath, Yongmei Chen, Amina Ali, Jacob Kagan, Sudhir Srivastava, Albert Dobi, David McLeod, Inger Rosner, Shiv Srivastava, Gyorgy Petrovics
Journal: Cancer Research (2018)

Abstract Introduction and Objectives: Prostate cancer (CaP) affects 1 in 7 men in their lifetime. 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 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, 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 CaP marker panel that is overexpressed equally well in AA and CA CaPs. Methods: Three platforms (RNA-Seq, NanoString, and qRT-PCR) were used for evaluating CaP-associated gene expression in CA and AA patients (N=144). Candidate genes with robust tumor overexpression (over 4-fold) in CaP in paired normal and tumor specimens from AA and CA patients were selected from NanoString and RNA-Seq 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 RT and preamplification followed by TaqMan PCR) was developed for noninvasive early detection of candidate genes in regular urine (non-DRE) using urinary exosomal RNA. Results: Tumor transcriptomes of CA patients consistently revealed elevated expression of PCA3 and AMACR. However, these genes had variable overexpression in the AA cohort. The top genes that were similarly overexpressed in tumors of AA and CA patients were validated by qRT-PCR in LCM 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 RNA-Seq data. Urinary exosome-based assay was developed and optimized for PSGR, DLX1, HOXC4, NKX2-3, as well as PCA3, PCGEM1, and ERG. All markers have been evaluated in a prospective cohort of 100 patients. In 36 AA patients a sensitivity of 78%, specificity of 68%, and AUC of 0.83 was achieved, surpassing currently used urine CaP markers of ERG and PCA3 in this cohort. 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. Source of Funding: This study is supported by NCI/EDRN ACN12011-001-0 and NCI RO1 CA162383-05 grants to S.S. Citation Format: Indu Kohaar, Sreedatta Banerjee, Lakshmi Ravindranath, Yongmei Chen, Amina Ali, Jacob Kagan, Sudhir Srivastava, Albert Dobi, David McLeod, Inger Rosner, Shiv Srivastava, Gyorgy Petrovics. Prostate cancer gene expression panel to address racial differences of molecular alterations in prostate cancer [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 A013.