An understanding of the prostate cancer pathophysiology for the identification of biomarkers that support an early diagnosis Herney Andrés García Perdomo MD MSc EdD PhD Director: Adalberto Sanchez BSc PhD Thesis presented to obtain the title of Doctor in Biomedical Sciences Universidad del Valle Santiago de Cali 2018 Introduction Prostate Cancer (CaP) is a condition whose etiology is multifactorial, it goes through genetic, infectious, as well as environmental, among others. Currently, PCa represents the most frequent cancer among men and the second in mortality, however, there are still multiple gaps in the knowledge of this condition. One of them is related to a molecular biomarker that allows early and accurate diagnosis of PCa. We have the Prostate Specific Antigen (PSA), however, its diagnostic performance alone is very low, and it must always be associated with digital rectal examination to obtain the best of both diagnostic methods. Problem statement Over the years, the focus of prostate cancer has been on the treatment. A patient with the condition is identified and they are offered invasive and non-invasive procedures that can generate adverse deleterious effects for the quality of life. Some efforts have been made for prevention without obtaining clear results according to the available evidence, and related to food and medication. Other efforts have focused on early diagnosis, with emphasis on the measurement of prostate- specific antigen (PSA) and digital rectal examination, however, there are already systematic reviews and meta-analyzes that show how population screening is not suggested of opportunity, given the large population that would have to sift to prevent a 10-year death (1). On the other hand but complementary, PSA and digital rectal examination, although they are fundamental elements, have an operative performance (Sensitivity, specificity, predictive values and probability reasons) that is not high and therefore, has room for false positives and negatives that would limit the diagnostic suspicion of prostate cancer. There are some biomolecules that have been studied both in Prostatic Hyperplasia and in Prostate Cancer, however its validity in the general population is still limited. There is only one identified genomic variation (AR-V7) that shows the probability of resistance to hormonal management with enzalutamide and abiraterone in patients with castration-resistant prostate cancer and therefore would require the use of chemotherapy(2–4). However, there is no biomolecule or genomic variant that can be distributed at the time as an early detection test or risk for the development of prostate cancer, which supports the realization of this work. Justification Prostate cancer (PC) is the second most common type of cancer in the world's male population (5). It is estimated that one in seven men will be diagnosed at the end of their life with CP, and one in 38 men will die as a result of this in the long term. Prostate Cancer is diagnosed more frequently as a consequence of the introduction in 1980 of the Prostate Specific Antigen (PSA) test as a diagnostic tool (3). During the last decade, there has been a notable decrease in mortality from prostate cancer in developed countries, but it has not been evidenced in developing countries. GLOBCAN in 2008 reported that in northern European countries (Denmark, Norway and Sweden) the diagnosis has 2 increased by 8.2% per year, with a mortality rate falling since 2000 of 3.1% per year (6). Similar data were evidenced in the United States and Canada, in which the incidence in the diagnosis of PC remains stable, but with a decrease in mortality of 4.3% and 3.1% respectively. On the other hand, in developing countries, mortality has increased (although there are trends towards an increase in diagnosis, mortality has increased in countries such as Colombia, 3.4% per year, Costa Rica, 3.4% year, Chile 2.8% per year and Cuba 5.5% per year) (6,7). With respect to the global context, Colombia has one of the lowest incidences in Latin America (6). Additionally, the mortality rate from prostate cancer has decreased in the last four years (7) and the largest number of cases reported originate in the cities of Bogotá, Valle and Antioquia (The most populated regions with the largest number of Urologists) (7). On the other hand, when considering an appetite for the treatment of localized prostate cancer, which is the focus of the present work, there are currently studies that show that there are no differences in 10-year mortality when comparing monitoring, radical surgery of prostate and radiotherapy (8). Even when classifying the patient according to the risk of disease progression (D'amico) (9), it is evidenced that when comparing radical prostatectomy with clinical observation, there are no differences at 10 years of follow-up for the specific cancer mortality outcome (10) in localized low risk PC. This is important to note because we still have gaps in knowledge. For several decades, urologists have performed radical surgeries that generate adverse events such as erectile dysfunction, urinary incontinence and urethral stricture. Given that we have elements of uncertainty such as those already demonstrated, we could consider the search for markers that identify which patients do not require a surgical procedure or those that have the risk, could be evaluated the possibility of genetic manipulation for prevention of prostate cancer. Recent and interesting investigations have been carried out that, although they are not yet conclusive, do encourage us to continue searching for risk markers and genomic alterations that allow us to classify and treat our patients even before developing the disease. Inhibitory markers such as mitochondrial autophagy have been identified, related to the poor prognosis in prostate cancer. Epigenetics have identified alterations in DNA methylation and microRNA expression that occur in the transition from the normal cell, precancerous, primary and metastatic tumors. The circulating DNA fragments are another important strategy to generate the genetic profile and sequencing of the genes of patients with prostate cancer(11). In such a way that we still have gaps in the knowledge of localized prostate cancer that deserve to be evaluated in works of this type. 3 Objectives: • To describe the frequency of Inherited DNA-repair genes and their variants associated to Prostate Cancer in a Cancer-Free Southwest Colombian population • To identify the association between the TMPRSS2:ERG fusion gene, their variants and the onset of localized prostate cancer. • To describe the frequency of allelic variants of TMPRSS2 gene in this population • To analyze the metabolomic profile in patients with malignant disturbances of the prostate compared with non-cancer patients. 4 Chapter 1: An updated and global review on prostate cancer Type of article: Narrative Review Authors: Herney Andrés García-Perdomo MD, MSc, EdD, PhD, FACS (1,2); James Alejandro Zapata-Copete MD (2,3); Adalberto Sanchez BSc PhD (1,4) Affiliations 1. Associate professor, Universidad del Valle- Cali, Colombia 2. UROGIV research group. Universidad del Valle, Cali, Colombia 3. Epidemiology Department, Universidad Libre- Cali, Colombia 4. School of Basic Sciences- Universidad del Valle- Cali, Colombia Introduction Prostate cancer given its frequency in the populations is a pathology of importance in public health not only national, but of high global impact (12). Given the difficulties of the Health System, the limited availability of specialists and the high prevalence of this condition, the knowledge of this condition should be the domain of any general practitioner, and should not remain in specialized medicine areas such as urology and oncology. However, the treatment in an integral way, must be given by centers of excellence in cancer (13). Objective To obtain an updated view through a detailed and up-to-date review of the epidemiology, risk factors, classification, diagnosis and treatment of prostate cancer. Methods A search was performed in Embase and Medline (through OVID) from January 2000 to March 2017. The keywords used were: "prostate" OR "prostate, neoplasm" AND "diagnosis" OR "treatment”. Additionally, an exhaustive manual evaluation of the bibliography provided in the articles found was also made. Results Epidemiology Prostate cancer (PCA) is the most frequent neoplasm in men in the world, and represents the second cause of cancer death in this population in the United States (14). It has an incidence of 131.5 / 100,000 inhabitants (14) with a race distribution of 123 / 100,000 inhabitants in the white and 208 / 100,000 inhabitants in the African American population (15). It is estimated that 1 in 7 men will be diagnosed throughout their life with PCA, and 1 in 38 men will die as a consequence of it (16). The GLOBCAN study reported that in the Northern European countries (Denmark, Norway and Sweden) the diagnosis of PCA has increased 8.2% per year, accompanied by a declining mortality of 3,1% per year since 2000 (6). In the United States and Canada, similar data have been found, with a stable incidence but with a decrease in mortality of 4.3% and 3.1% respectively; however, 5 in developing countries, mortality has increased (6,7). Regarding the national epidemiology, Colombia has one of the lowest incidences of PCA in Latin America and a proportion of 28% between incidence and mortality for it, very close to the world average of 28.6% and lower than countries like Ecuador (40.41%), Cuba (46.65%) and Peru (37.74%) (6). Mortality has decreased in the last four years (7) and the regions with the highest number of CAP patients reported are Bogotá, Valle and Antioquia (The most populated regions and with the largest number of Urologists) (7,16). Risk factors Race Black patients have a higher prevalence of PCA (17), furthermore, they present at younger ages with greater tumor volume, a greater prostatic antigen level and worse prognosis (18,19).