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CHAPTER 90: EPIDEMIOLOGY, ETIOLOGY, and PREVENTION of PROSTATE CANCER Campbell’s Urology Review Sundip Patel EPIDEMIOLOGY • Most common visceral malignant neoplasm in US men. • Lifetime risk – 17.6% WHITES 2.8% DEATHS – 20.6% AFRICAN AMERICANS 4.7% DEATHS Annual Death rates 30/100,000 EPIDEMIOLOGY • Worldwide , prostate cancer is 4th most common male malignant neoplasm • Lowest rate is in Asia (1.9/100,000) • Highest in North America and Scandinavia, esp AA (272/100,000) • CaP rarely diagnosed in men <50. • Peak incidence b/w 70-74 years • 85% diagnosed after age 65 years EPIDEMIOLOGY • Now, a more favorable stage at presentation • Incidence of local regional disease is increased, metastatic disease incidence is decreased. • Non-palpable cancers account for 75% of newly diagnosed disease • Thus, 5/10 year survival rates improved • Effects on mortality - controversial RISK FACTORSinfluences • Genetic and environmental • GENETIC INFLUENCES – Risk increased according to number of affected family members, relatedness, age of infliction – Hereditary FORM • If dx at <55y/o; stronger familial clustering; number of family members and age of onset is most important EPIDEMIOLOGY – GENES • HPC1 best cited; RNase L enzyme; Type I interferons, 2-5A synthetases, R462Q, Arginine to Glutamine substitution • HPC1 autosomal dominant with high penetrance • SR-A/MSR MIC1 --- MEDIATORS OF InflamaTION • PON1 • CHEK2/BRCA2/OGG1 --- DNA REPAIR Inflammation, infection, genetic susceptibility • Prostate cancer may be associated with hx of STD or prostatitis • Proliferative inflammatory atrophy are frequent in prostate specimens • Compromised cellular defenses against inflammatory oxidants may initiate and perpetuate prostatic carcinogenesis Molecular Epidemiology • Androgens – Affects proliferation and differentiation of luminal epithelium – Long term ABSENCE of androgens are protective • Estrogens – Could be protective or teratogenic – Phytoestrogens may be beneficial Molecular Epidemiology • Insulin – Like Growth Factor Axis – IGF-1 inhibits apoptosis in normal prostate – Its protein, IGFBP-3 can be cleaved by PSA, reducing its pro-apoptic activity • Leptin Produced by adipocytes Stimulates DU145 and PC3 prostate cancer cell lines Molecular Epidemiology • Vitamin D in relation to cancer risk (protective) – Higher CaP mortality rate in men living in northern latitudes – Occurs more frequently in older men – African Americans have the highest worldwide incidence – Increased dairy intake assoicted with prostate cancer – Native Japanese – high vit D diet- have low incidence of prostate cancer Epidemiology • Sexual Activity – Unknown effect • Vasectomy – Predispostion to cancer • Smoking – Risk factor for prostate cancer • Diet – Strong effect on CaP Epidemiology • Dietary Fat – Polyunsaturated fat consumption correlated highly with prostate cancer • Obesity – INC BMI demonstrate oxidative stress – Lower PSA concentrations in higher BMI patients • Alcohol – 1-3 glasses of red wine may be protective Etiology and Molecular Genetics • CaP exists in 2 forms – Histologic – similar prevalence worldwide – Clinically Evident Form – prevalence variable • Androgen Influence – 1o androgen is DIHYDROTESTOSTERONE – Testosterone [type 2] 5α-Reductase Dihydrotestosterone – Insufficient exposure to DIHYDROTESTOSTERONE is protective Etiology and Molecular Genetics • Stem Cells – Likely exist and are being researched for both prevention and therapeutic purposes • Epigenetic change – Involves a change in expression without altering the actual DNA • Methylation, chromatin remodeling, histone modification, RNA interference Etiology and Molecular Genetics • Cyclooxygenase [Cox-2] – Enzymes that help produce prostaglandin, which is used during an inflammatory response – Prostate cancers express more Cox-2 – NSAIDS inhibit COX-2 expression and may be protective Etiology and Molecular Genetics Somatic Mutations Associated with Tumor Initiation and Progression – Androgen receptor – Glutathione STransferase – NKX3-1 – P27 – PTEN – Classical Oncogenes – Vascular Endothelial Growth Factor – Telomerase – E-Cadherin – Α-Methylacyl-CoA Racemase Etiology and Molecular Genetics • Prostate Specific Membrane Antigen – Possible immunotherapeutic agent • Epidermal Growth Factor – Associated with prostate cancer • EZH2 – Increase during CaP progression CHEMOPREVENTION • Prostate Cancer Prevention Trial – Tested hypothesis that treatment with finasteride prevents prostate cancer – 19000 men with normal DRE and PSA were randomly assigned to daily medication vs placebo – Trial stopped 15 months early – Risk reduction of 25% reached in medication arm CHEMOPREVENTION • Antioxidants and Selenium and Vitamin E – Selenium can decrease the risk of prostate cancer • Vitamin E [α-tocopherol] – Major lipid-soluble antioxidant in cell membranes – Proposed to induce cell cycle arrest and direct antiandrogen activity CHEMOPREVENTION • Soy – Have isoflavones which inhibit prostatic epithelial cell growth, downregulate androgen genes, and reduce tumor growth • Lycopene – Potent antioxidant activity • Mixed evidence of lowering risk of prostate cancer • Green Tea – Inferred to help prevent prostate cancer based on low incidence among asian men with higher intake of green tea