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PROSTATE CANCER: EPIDEMIOLOGY & PATHOGENESIS

Epidemiology§§§

• Incidence
  • Highest in countries with the highest rates of screening
  • Worldwide
    • 2nd most common visceral malignancy in men
    • Estimated incidence 2020: 1,414,259
  • US
    • Most common visceral malignancy in men
    • Estimated incidence 2021: 248,530
      • ≈1/8 males are diagnosed with prostate cancer during their lifetime
  • Canada Statistics
    • Most common malignancy in males
      • Followed by lung and bronchus (13.2%) and colorectal (12.9%)
      • In females, most common cancers are breast (25%), lung and bronchus (13.5%), and colorectal (10.9%)
    • Estimated cancer incidence 2020: 220,400
    • Estimated prostate cancer incidence 2020: 23,300
      • 11.3% (≈1/9 men) lifetime probability of prostate cancer diagnosis in males
  • Trends in incidence
    • PSA was discovered in 1979 and was licensed as a test by the FDA in 1986. Thereafter, the incidence of prostate cancer increased significantly, peaking in 1992, ≈5 years after the introduction of the PSA test.
    • Incidence then declined until 1995 (screening responsible for decrease i.e. there were now fewer people with prostate cancer in the source population as they had been screen-detected)
    • Since 1995, incidence increased at a rate similar to pre-PSA screening era, and fluctuated year-to-year since 2001 until 2011 when the draft of the 2012 US Preventative Services Task Force recommendations came out recommending against PSA screening in all males (grade D).
  • Median age at diagnosis: 67
    • Incidence has increased in younger males and decreased in older males, largely account for by PSA screening
    • Men with prostate cancer younger than 50 years account for 2% of all cases
• Mortality
  • Cause of death in ≈3% of US men
    • Only ≈16% of males diagnosed with prostate cancer ultimately die of it, demonstrating the indolent course of most prostate cancers
    • Most common cause of mortality in males with prostate cancer is cardiac disease§
  • 2nd leading cause of cancer-related death (lung is 1st);
  • Trends in Mortality
    • Decreasing since 2001
  • Average age of death from prostate cancer is 77 years
  • Mortality in African-Americans 2.4x higher than Caucasians
• Trends in stage
  • There has been clinical and pathological stage migration over time largely due to PSA screening
  • At the time of diagnosis§
    • ≈80% present with localized disease
    • ≈12% present with regional disease
    • ≈ 5% present with metastatic disease

Pathogenesis

• Risk factors (5):

1. Age
2. Ethnicity
   • Incidence in African-American > Caucasians > Hispanic/Latino > Asian-American
   • Men of Asian descent living in the US have a lower incidence compared to white Americans, but their risk is higher than that of Asians living in Asia, suggesting a dietary, lifestyle, environmental factor
3. Family history
   • ≈15% of prostate cancer patients have the familial or hereditary form
   • Risk varies according to the number of affected family numbers, their degree of relatedness, and the age at which they were affected
     • Father affected: relative risk (RR) 2.2x
     • Brother affected: RR 3.4x
     • First-degree family member affected, age <65 at diagnosis: RR 3.3x
     • >2 first-degree relatives affected: RR 5.1x
     • Second-degree relative affected: RR 1.7x
4. Germline mutations
   • Genes that substantially increase risk:
     1. HOXB13
     2. BRCA
     • BRCA-associated, especially BRCA2, cancers are more aggressive
       • More likely to present with higher grade, locally advanced, and metastatic disease, and have worse cancer-specific survival and metastasis-free survival after prostatectomy
       • 2-6x increased lifetime risk (BRCA2 > BRCA1)
       • Increased risk of metastatsis and prostate cancer-specific mortality§
     • BRCA-cancers: breast, ovarian, pancreatic, prostate, melanoma
   • Incidence of germline mutations in genes mediating DNA-repair processes in prostate cancer (2016)
     • Population: 692 men
     • Results:
       • Incidence of germline mutations in genes mediating DNA-repair processes was significantly higher in males with metastatic prostate cancer (11.8%) compared to males with localized prostate cancer (4.6%) and the general population (2.7%)
     • Pritchard et al. NEJM 2016
   • Lynch syndrome§
     • Due to mutation in mismatch repair genes
     • Associated cancers: (8) colonic (most common), endometrial (second most common), prostate, urothelial, adrenal, gastric, pancreatic, uterine, ovarian, and sebaceous carcinomas
5. Inflammation
   • Likely contributes to development and progression of early-stage disease
   • Potential triggers for inflammation include dietary carcinogens (especially from cooked meats), estrogens, and infectious agents
   • Studies assessing the association between infection and prostate cancer have shown mixed results; some data suggest that history of STIs and prostatitis is associated with increased risk of prostate cancer
• Polymorphisms in both synthetic and metabolic genes, including the androgen receptor (AR), the 5-alpha reductase type 2 isoenzyme, and genes involved in testosterone biosynthesis, have been reported to affect risk
• Insulin-like growth factor axis is important in prostate cancer risk and progression
• Polymorphisms conferring lower vitamin D receptor activity are associated with increased risk for prostate cancer; vitamin D and its interaction with its receptor modulates disease aggressiveness
• Smoking increases risk and is associated with worse biochemical recurrence, metastasis, and cancer-specific mortality
• Mixed results with alcohol

Molecular Genetics

• Biologic functions of known prostate cancer susceptibility genes include:
  1. Control of the inflammatory response
  2. Homeobox genes
  3. DNA repair mechanisms
  4. Susceptibility to infection
• Most common gene fusion identified in localized prostate cancer involves TMPRSS2 or other promoters (SLC45A3, HERPUD1, or NDRG) fused to ERG (ETS-related gene)
• The TMPRSS2 gene is prostate specific, and is expressed in both benign and malignant prostatic epithelium;
• TMPRSS2:ERG fusion gene is detected in ≈50% of prostate cancers
• TMPRSS2-ERG fusion gene is present in prostate stem cells
• TMPRSS2 expression has been shown to be induced by androgens
• TRMPSS2-related gene fusions are highly specific for the presence of prostate cancer
• Most common point mutations in prostate cancer are mutations in SPOP, which encodes a subunit of ubiquitin ligase
• Current evidence suggests that most prostate cancer is polygenic in origin. GWAS studies have identified more than 70 risk alleles and chromosomal loci, many of which occur in non-coding areas of the genome. A variety of genes implicated in prostate cancer initiation and progression include
• Hypermethylation of
• Hormonal response genes (ERαA, ERβ, and RARβ)
• Genes controlling the cell cycle (CyclinD2 and 14-3-3σ)
• Tumor cell invasion/tumor architecture genes (CD44)
• DNA repair genes (GSTpi, GPX3, and GSTM1)
• Tumor suppressor genes (APC, RASSF1α, DKK3, p16INK4?−α, E-cadherin, and p57WAF1)
• Signal transduction genes (EDNRB and SFRP1)
• Inflammatory response genes (PTGS/COX2)
• Hypomethylation of CAGE, HPSE, and PLAU
• Histone hypoacetylation of CAR, CPA3, RARB, and VDR
• Histone methylation of GSTP1 and PSA
• Epigenetic mechanisms active in prostate cancer include:
  1. Chromatin remodeling
  2. Promoter hypomethylation and hypermethylation
  3. MicroRNAs that lead to gene silencing
  4. Long non-coding RNAs

Questions

1. What proportion of US males are diagnosed with prostate cancer during their lifetime?
2. Which germline mutations are associated with increased risk of prostate cancer?
3. What are the BRCA2 related cancers?
4. Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain?
5. What is the most common gene fusion identified in localized prostate cancer?

 

Answers

1. What proportion of US males are diagnosed with prostate cancer during their lifetime?
   • ≈1/7-1/9
2. Which germline mutations are associated with increased risk of prostate cancer?
   • HOXB13 and BRCA2
3. What are the BRCA2 related cancers?
   • Breast, ovarian, prostate, pancreatic, melanoma
4. Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain?
   • Type 2 is primarily in the prostate and other genital tissues such as the epididymis, genitalia, seminal vesicle, testis, but also in liver, uterus, breast, hair follicles, and placenta
   • Type 1 is primarily in the non-genital skin and liver, and also found in the prostate, testis, and brain
5. What is the most common gene fusion identified in localized prostate cancer?
• TMPRSS2 fused to ERG

Next Chapter: Prevention

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 107