title: The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy.
abstract: ERG and androgen receptor (AR) are known to function cooperatively in prostate cancer (PCa) progression. However, the prognostic value of combined ERG and AR expression and potential pathways are not well characterized. We assessed ERG and AR protein expression by immunohistochemistry in a cohort of 312 men with PCa diagnosed by transurethral resection of the prostate (TURP). Patients were divided into those with no prior hormonal treatment (designated as PCa/AdvPCa) vs. those with castrate-resistant PCa (CRPC) undergoing channel TURP to relieve obstructive symptoms. The expression status was correlated with various clinical-pathological parameters. The Swedish watchful-waiting cohort was used for validation and characterization of potential gene signatures associated with ERG and AR.   Patients with combined ERG-positive/AR high expression profile demonstrated higher rates of PCa-specific mortality (PCSM) compared with patients with ERG-negative/AR low in patients with no prior treatment (n = 90, P = 0.032), but this was attenuated in the overall cohort which included the CRPC subgroup (n = 125, P = 0.096). The prognostic significance to PCSM was validated in the Swedish watchful waiting cohort in univariate (HR: 3.3; 95% CI: 1.9-5.6, P = 4.25E-5) and multivariate analysis (HR: 2; 95% CI: 0.97-4.1, P = 0.057), which included Gleason score. ERG/AR overexpression status characterized 152 genes signatures including WNT, PI3K/AKT and chemokine signaling pathways known to be deregulated in PCa. In conclusion, combined ERG/AR overexpression signifies a class of patients at highest-risk of PCSM with specific key genetic alteration likely responsible for disease progression. The prognostic value of combined ERG/AR overexpression and its associated genes should be further investigated as potential prognostic and therapeutic targets in prostate cancer progression.
authors: Department of Pathology and Laboratory Medicine; University of Calgary and Calgary Laboratory Services; Calgary, AB Canada.
authors: Kuo-Cheng
authors: KC
authors: Huang
authors: The Prostate Cancer Center; Calgary, AB Canada.
authors: Mohammed
authors: M
authors: Alshalalfa
authors: Department of Pathology and Laboratory Medicine; University of Calgary and Calgary Laboratory Services; Calgary, AB Canada; The Prostate Cancer Center; Calgary, AB Canada; Department of Pathology; Faculty of Medicine; Zagazig University; Zagazig, Egypt.
authors: Samar A
authors: SA
authors: Hegazy
authors: Department of Pathology and Laboratory Medicine; University of Calgary and Calgary Laboratory Services; Calgary, AB Canada.
authors: Michael
authors: M
authors: Dolph
authors: Department of Urology; University of Calgary; Calgary, AB Canada; The Prostate Cancer Center; Calgary, AB Canada.
authors: Bryan
authors: B
authors: Donnelly
authors: Department of Pathology and Laboratory Medicine; University of Calgary and Calgary Laboratory Services; Calgary, AB Canada; Departments of Oncology, Biochemistry and Molecular Biology; Calgary, AB Canada; Southern Alberta Cancer Institute and Tom Baker Cancer Center; Calgary, AB Canada; The Prostate Cancer Center; Calgary, AB Canada.
authors: Tarek A
authors: TA
authors: Bismar
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000172:deficiency*; D018925:Chemokines / Q000378:metabolism; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000175:diagnosis / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D020728:Transurethral Resection of Prostate; D057832:Watchful Waiting; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; D018925:Chemokines; C072312:ERG protein, human; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051153:Wnt Proteins; D007987:Gonadotropin-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen
keywords: ERG protein expression; Gleason score; cancer specific mortality; hormone therapy; immunohistochemistry; tumor volume