Prostate Cancer: Epidemiology and Pathogenesis
PROSTATE CANCER: EPIDEMIOLOGY & PATHOGENESIS
Epidemiology<a href="https://pubmed.ncbi.nlm.nih.gov/33538338/">§</a><a href="https://seer.cancer.gov/statfacts/html/prost.html">§</a><a href="https://www.ncbi.nlm.nih.gov/pubmed/32122974">§</a>
- 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
- Most common malignancy 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 <a href="../../CNotes/Prostate Cancer/pcascreening.html#uspstf">US Preventative Services Task Force recommendations</a> 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<a href="https://pubmed.ncbi.nlm.nih.gov/23795786/">§</a>
- 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
- Cause of death in ≈3% of US men
- Trends in stage
- There has been clinical and pathological stage migration over time largely due to PSA screening
- At the time of diagnosis<a href="https://seer.cancer.gov/archive/csr/1975_2014/browse_csr.php?sectionSEL=23&pageSEL=sect_23_table.08.html#table3">§</a>
- ≈80% present with localized disease
- ≈12% present with regional disease
- ≈ 5% present with metastatic disease
<a name="pcriskfactors">Pathogenesis</a>
- Risk factors (5):
- Age
- 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
- 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
- Germline mutations
- Genes that substantially increase risk:
- HOXB13
- 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<a href="https://pubmed.ncbi.nlm.nih.gov/25454609/">§</a>
- <a name="brcacancers">BRCA-cancers: breast, ovarian, pancreatic, prostate, melanoma</a>
- <a name="pritchard2016">Incidence of germline mutations in genes mediating DNA-repair processes in prostate cancer (2016)</a>
- 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%)
- <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1603144">Pritchard et al. NEJM 2016</a>
- Lynch syndrome<a href="https://cebp.aacrjournals.org/content/23/3/437 ">§</a>
- 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
- Genes that substantially increase risk:
- 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:
- Control of the inflammatory response
- Homeobox genes
- DNA repair mechanisms
- 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:
- Chromatin remodeling
- Promoter hypomethylation and hypermethylation
- MicroRNAs that lead to gene silencing
- Long non-coding RNAs
Questions
- What proportion of US males are diagnosed with prostate cancer during their lifetime?
- Which germline mutations are associated with increased risk of prostate cancer?
- What are the BRCA2 related cancers?
- Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain?
- What is the most common gene fusion identified in localized prostate cancer?
Answers
- What proportion of US males are diagnosed with prostate cancer during their lifetime?
- ≈1/7-1/9
- Which germline mutations are associated with increased risk of prostate cancer?
- HOXB13 and BRCA2
- What are the BRCA2 related cancers?
- Breast, ovarian, prostate, pancreatic, melanoma
- 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
- What is the most common gene fusion identified in localized prostate cancer?
- TMPRSS2 fused to ERG
Next Chapter: <a href="pcaprevention.html">Prevention</a>
References
- Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 107