Identification of Genomic Biomarkers for Improving Risk Stratification of Low- and Intermediate-Risk Prostate Cancer Patients By Walead Ebrahimizadeh Faculty of Medicine, Division of Experimental Surgery McGill University, Montreal August 2019 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Ph.D. © Walead Ebrahimizadeh 2019 Table of Contents Table of Contents ........................................................................................................................................... I List of Tables .............................................................................................................................................. IV List of Figures .............................................................................................................................................. V ABSTRACT ................................................................................................................................................ VI RÉSUMÉ .................................................................................................................................................. VII ACKNOWLEDGMENTS ....................................................................................................................... VIII CONTRIBUTION TO ORIGINAL KNOWLEDGE.................................................................................. IX CONTRIBUTION OF AUTHORS ........................................................................................................... XII 1. CHAPTER 1 - LITERATURE REVIEW ............................................................................................. 1 1.1. OVERVIEW OF THE PROSTATE ............................................................................................. 1 1.1.1. Anatomy ................................................................................................................................ 1 1.1.1.1. Lobes of the prostate ..................................................................................................... 2 1.1.1.2. Zones of the prostate ..................................................................................................... 3 1.1.2. Prostate development ............................................................................................................ 4 1.1.3. Prostate function ................................................................................................................... 7 1.1.4. Common diseases of the prostate .......................................................................................... 7 1.2. PROSTATE CANCER ................................................................................................................. 9 1.2.1. Epidemiology ........................................................................................................................ 9 1.2.2. Risk factors ......................................................................................................................... 10 1.2.2.1. Age .............................................................................................................................. 10 1.2.2.2. Family history ............................................................................................................. 10 1.2.2.3. Ethnicity ...................................................................................................................... 11 1.2.2.4. Diet and environmental factors ................................................................................... 11 1.2.3. Diagnosis of PCa ................................................................................................................. 11 1.2.3.1. PSA ............................................................................................................................. 12 1.2.3.2. Digital Rectal Exam .................................................................................................... 13 1.2.3.3. Transrectal ultrasound (TRUS)-guided biopsies ......................................................... 14 1.2.4. Prognostic Tools of PCa ..................................................................................................... 16 1.2.4.1. Gleason score (GS) ..................................................................................................... 16 1.2.4.2. Tumor, Lymph Node and Metastases (TNM) Staging ................................................ 22 1.2.5. Risk stratification models .................................................................................................... 25 1.2.6. Common treatment options ................................................................................................. 26 1.2.6.1. Active surveillance ...................................................................................................... 27 I 1.2.6.2. Radical prostatectomy (RP) ........................................................................................ 31 1.2.6.3. Radiotherapy ............................................................................................................... 32 1.2.6.4. Androgen deprivation therapy and other therapeutic options ..................................... 34 1.3. BIOMARKERS OF PCa ............................................................................................................. 37 1.3.1. PSA ..................................................................................................................................... 38 1.3.2. Prostate cancer antigen 3 (PCA3) ....................................................................................... 39 1.3.3. Prostate stem cell antigen (PSCA) ...................................................................................... 39 1.3.4. Prostate-specific membrane antigen (PSMA) ..................................................................... 40 1.3.5. α-Methylacyl-CoA racemase (AMACR) ............................................................................ 41 1.3.6. E26 transformation-specific (ETS) gene fusion .................................................................. 42 1.3.7. DNA copy number alteration (CNA) .................................................................................. 43 1.4. CNAs RELEVANT TO PROSTATE TUMOR BIOLOGY ....................................................... 44 1.4.1. RWDD3 (1p21.3) ................................................................................................................ 45 1.4.2. PDZD2 (5p13.3).................................................................................................................. 46 1.4.3. GTF2H2 (5q13.2)................................................................................................................ 49 1.4.4. CHD1 (5q15-q21.2) ............................................................................................................ 52 1.4.5. MAP3K7 (6q15) .................................................................................................................. 53 1.4.6. WRN (8p12) ........................................................................................................................ 55 1.4.7. NKX3-1 (8p21.2) ................................................................................................................. 59 1.4.8. MYC (8q24.21) .................................................................................................................... 61 1.4.9. PTEN (10q23.31) ................................................................................................................ 64 1.4.10. CDKN1B (12p13.1) ............................................................................................................. 67 1.4.11. RB1 (13q14.2) ..................................................................................................................... 69 1.4.12. PDPK1 (16p13.3)................................................................................................................ 72 1.4.13. GABARAPL2 (16q23.1) ...................................................................................................... 74 1.1.14. TP53 (17p13.1) ................................................................................................................... 77 1.5. CNA DETECTION METHODS ................................................................................................ 80 2. CHAPTER 2 - RATIONALE, HYPOTHESIS, OBJECTIVES AND METHODS ........................... 84 2.1. RATIONALE ................................................................................................................................... 84 2.2. HYPOTHESIS ............................................................................................................................ 87 2.3. OBJECTIVES ............................................................................................................................. 87 2.4. PROPOSED METHODOLOGY ................................................................................................ 88 3. CHAPTER 3 – MANUSCRIPT ONE ................................................................................................ 93 3.1. Abstract ............................................................................................................................................ 94 3.2. Introduction ................................................................................................................................