Editing Prostate Cancer: Epidemiology and Pathogenesis (section)

== Pathogenesis ==

* '''<span style="color:#ff0000">Risk factors (5 (only hereditary risk factors mentioned in 2023 AUA Early Detection of Prostate Cancer Guidelines):</span>'''
*# '''<span style="color:#ff0000">Inherited (3):</span>'''
*##'''<span style="color:#ff0000">Germline mutations</span>'''
*##* '''<span style="color:#ff0000">Frequency of germline mutations in genes mediating DNA-repair processes by population:[https://www.nejm.org/doi/full/10.1056/NEJMoa1603144]</span>'''
*##**'''Metastatic prostate cancer: 12%'''
*##**'''Localized prostate cancer: 5%''' 
*##**'''General population: 2.7%'''
*##*True hereditary disease: > 3 cases in the same family, PCa in three successive generations, or > 2 men diagnosed with PCa < 55 yrs[https://uroweb.org/guidelines/prostate-cancer/chapter/epidemiology-and-aetiology]
*##*Hereditary prostate cancer is associated with earlier onset (6-7 years) but not more aggressive disease.[https://uroweb.org/guidelines/prostate-cancer/chapter/epidemiology-and-aetiology]
*##*'''<span style="color:#ff0000">BReast CAncer Genes (BRCA)</span>'''
*##** '''BRCA1 and BRCA2 variants have increased risks of both prostate cancer incidence and progression.'''
*##*** 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
*##*** Increased risk of metastasis and prostate cancer-specific mortality[https://pubmed.ncbi.nlm.nih.gov/25454609/]
*##*** '''Stronger association between BRCA2, compared to BRCA1, with both incidence and aggressive cancer'''
*##*** '''Systematic PSA screening is indicated'''
*##** '''<span style="color:#ff0000">Hereditary breast and ovarian cancer syndrome (HBOC)</span>'''
*##*** '''Most commonly associated with mutations in either the BRCA1 or BRCA2 gene'''
*##*** '''<span style="color:#ff0000">Associated cancers (5):[https://www.ncbi.nlm.nih.gov/books/NBK1247/]</span>'''
*##**# '''<span style="color:#ff0000">Breast (male and female)</span>'''
*##**# '''<span style="color:#ff0000">Ovarian</span>'''
*##**# '''<span style="color:#ff0000">Prostate</span>'''
*##**# '''<span style="color:#ff0000">Pancreatic</span>'''
*##**# '''<span style="color:#ff0000">Melanoma</span>'''
*##* '''<span style="color:#ff0000">Lynch syndrome</span>[https://cebp.aacrjournals.org/content/23/3/437]'''
*##** '''Also known as hereditary non-polyposis colorectal cancer (HNPCC)'''
*##** '''Due to inherited mutations in genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) that affect DNA mismatch repair'''
*##** '''<span style="color:#ff0000">Associated cancers (10)</span>[https://www.ncbi.nlm.nih.gov/books/NBK431096/]'''
*##**#'''<span style="color:#ff0000">Colorectal</span>'''
*##**#'''<span style="color:#ff0000">Gastric</span>'''
*##**#'''<span style="color:#ff0000">Ovarian</span>'''
*##**#'''<span style="color:#ff0000">Small bowel</span>''' 
*##**# '''<span style="color:#ff0000">Urologic</span>'''
*##**##'''<span style="color:#ff0000">Upper tract urothelial carcinoma</span>'''
*##**##'''<span style="color:#ff0000">Bladder[https://pubmed.ncbi.nlm.nih.gov/36672455/ §]</span>'''
*##**##'''<span style="color:#ff0000">Prostate[https://pubmed.ncbi.nlm.nih.gov/23530095/ §]</span>'''
*##**#'''<span style="color:#ff0000">Biliary tract</span>'''
*##**# '''<span style="color:#ff0000">Pancreatic</span>'''
*##**# '''<span style="color:#ff0000">Brain cancers (glioblastoma)</span>'''
*##**#'''<span style="color:#ff0000">Sebaceous gland adenomas</span>''' 
*##**#'''<span style="color:#ff0000">Keratoacanthomas</span>''' 
*##* '''<span style="color:#ff0000">Other mutations</span>'''
*##** '''<span style="color:#ff0000">ATM, MLH1, MSH2, MSH6, PMS2, HOXB13, NBS1, and CHEK2</span>'''
*##*** '''<span style="color:#ff0000">These mutations need further study to evaluate their role in prostate cancer incidence and aggressiveness</span>'''
*##'''<span style="color:#ff0000">Family history</span>'''
*##* '''≈15% of prostate cancer patients have the familial or hereditary form'''
*##* Familial prostate cancer is defined as > 2 first- or second-degree relatives with PCa on the same side of the pedigree[https://uroweb.org/guidelines/prostate-cancer/chapter/epidemiology-and-aetiology]
*##*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
*##* '''<span style="color:#ff0000">Criteria for "strong" family history (2):</span>'''
*##*#'''<span style="color:#ff0000">≥1 brother or father OR ≥2 male relatives with one of the following (3):</span>'''
*##*##'''<span style="color:#ff0000">Diagnosed with prostate cancer at age <60 years</span>'''
*##*##'''<span style="color:#ff0000">Any of whom died of prostate cancer</span>'''
*##*##'''<span style="color:#ff0000">Any of whom had metastatic prostate cancer.</span>'''
*##*#'''<span style="color:#ff0000">Family history of other cancers with ≥2 cancers in hereditary breast and ovarian cancer syndrome or Lynch syndrome spectrum.</span>'''
*##*#* '''See associated cancers above'''
*##* '''<span style="color:#ff0000">Patients with a "strong" family history should ideally be genotyped</span>[https://pubmed.ncbi.nlm.nih.gov/37096582/]'''
*##** '''Genotype is to ascertain whether there is presence of a pathogenic variant (e.g., BRCA1/2, Lynch Syndrome, ATM, CHEK2) or one or more of a growing set of identified germline DNA damage-repair mutations found in patients with metastatic prostate cancer diagnoses.'''
*##'''<span style="color:#ff0000">Ethnicity</span>'''
*##* '''<span style="color:#ff0000">Incidence in Blacks > Whites</span> > Hispanics > Asian-Americans'''
*##**Estimated incidence in Blacks is 1.7x higher than Whites and 2x higher than Hispanics[https://pubmed.ncbi.nlm.nih.gov/36633525/]
*##* Males 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
*#'''<span style="color:#ff0000">Age</span>'''
*#*Prevalence of prostate cancer from autopsy series in males aged[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485977/][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682465/]
*#** <30: 5%
*#** 70-79: 36% of Caucasians and 51% of African-Americans
*#** >79: 59%
*# '''<span style="color:#ff0000">External (1):</span>'''
*##'''<span style="color:#ff0000">Inflammation</span>'''
*##* 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