3. EPIDEMIOLOGY AND AETIOLOGY
Prostate cancer is the second most commonly diagnosed cancer in men, with an estimated 1.4 million diagnoses worldwide in 2020 [7,8]. A systematic review of autopsy studies reported a prevalence of PCa at age < 30 years of 5% (95% confidence interval [CI]: 3–8%), increasing by an odds ratio (OR) of 1.7 (1.6–1.8) per decade, to a prevalence of 59% (48–71%) by age > 79 years . There is variation in the frequency of autopsy-detected PCa between men with different ethnical backgrounds and geographical areas (e.g., 83 in white US males vs. 41 in Japan at age 71–80) .
The variation in incidence of PCa diagnosis is even more pronounced between different geographical areas, driven by rate of prostate-specific antigen (PSA) testing and influenced by (inter)national organisations‘ recommendations on screening (see Section 5.1) . It is highest in Australia/New Zealand and Northern America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2, respectively), and in Western and Northern Europe (ASRs of 94.9 and 85, respectively). The incidence is low in Eastern and South-Central Asia (ASRs of 10.5 and 4.5, respectively), but rising . Rates in Eastern and Southern Europe were low but have also shown a steady increase [8,10]. Besides PSA testing, incidence is also dependent on the age of the population, geography and ethnicity.
There is relatively less variation in mortality rates worldwide, although rates are generally high in populations of African descent (e.g., Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 19 and 14), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [8,13]. Mortality due to PCa has decreased in most Western nations but the magnitude of the reduction varies between countries .
3.2.1. Family history/hereditary prostate cancer
Family history and ethnic background are associated with an increased PCa incidence suggesting a genetic predisposition [14,15]. Men of African ancestry in the Western world demonstrate more unfavourable outcomes due to a combination of biological, environmental, social, and health care factors . They are more likely to be diagnosed with more advanced disease  and upgrade after prostatectomy was more frequent as compared to Caucasian men (49% vs. 26%) . Racial disparities in development of, prevention of, and therapies for PCa may exist. It should be kept in mind that many PCa studies include either small percentages of men from other origin than Caucasians or focus on highly specific other groups .
Only a small subpopulation of men with PCa have true hereditary disease (> 3 cases in the same family, PCa in three successive generations, or > 2 men diagnosed with PCa < 55 yrs). Hereditary PCa (HPCa) is associated with a six to seven year earlier disease onset but the disease aggressiveness and clinical course does not seem to differ in other ways [14,20]. In a large USA population database, HPCa (reported by 2.18% of participants) showed a relative risk (RR) of 2.30 for diagnosis of any PCa, 3.93 for early-onset PCa, 2.21 for lethal PCa, and 2.32 for clinically significant PCa (csPCa) . These increased risks with HPCa were higher than for familial PCa (> 2 first- or second-degree relatives with PCa on the same side of the pedigree), or familial syndromes such as hereditary breast- and ovarian cancer and Lynch syndrome. With the father as well as two brothers affected, the probability of high-risk PCa at age 65 was 11.4% (vs. a population risk of 1.4%), and for any PCa 43.9% vs. 4.8%, in a Swedish population-based study .
184.108.40.206. Germline mutations and prostate cancer
Genome-wide association studies have identified more than 100 common susceptibility loci contributing to the risk for (aggressive) PCa [23-27]. Clinical cohort studies have reported rates of 15% to 17% of cases harbour any germline mutations independent of stage [28,29]. Based on clinical genetic data from men with PCa unselected for metastatic disease undergoing multigene testing across the US, it was found that 15.6% of men with PCa have pathogenic variants identified in genes tested ([Breast Cancer genes] BRCA1, BRCA2, HOXB13, MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men have germline pathogenic variants in DNA repair genes (see Table 3.1) . Pathogenic variants were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%) .
The frequency and distribution of positive germline variants of 3,607 unselected PCa patients was reported and showed that 620 (17.2%) had a pathogenic germline variant . A carrier rate of 16.2% was found in unselected patients at diagnosis of metastatic castrate-resistant PCa (mCRPC) who were screened for DNA damage repair (DDR) mutations in 107 genes .
Among unselected men with metastatic PCa, an incidence of 11.8% was found for germline mutations in genes mediating DNA-repair processes . Targeted genomic analysis of genes associated with an increased risk of PCa could offer options to identify families at high risk [32,33].
A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed BRCA2 association with aggressive PCa . An analysis of the outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 non-carriers) showed that PCa with germline BRCA1/2 mutations were more frequently associated with ISUP > 4, T3/T4 stage, nodal involvement, and metastases at diagnosis than PCa in non-carriers . BRCA-susceptibility gene mutation carriers were also reported to have worse outcome when compared to non-carriers after local therapy . In a retrospective study of 313 patients who died of PCa and 486 patients with low-risk localised PCa, the combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than in localised PCa patients (1.44%) . The rate of PCa among BRCA1 carriers was more than twice as high (8.6% vs. 3.8%) compared to the general population, in contrast to findings of the prospective IMPACT study (Identification of Men With a Genetic Predisposition to ProstAte Cancer (see Chapter 5) .
Table 3.1: Germline mutations in DNA repair genes associated with increased risk of prostate cancer
Prostate cancer risk
• up to 12 % of men with metastatic PCa harbour germline mutations in 16 genes (including BRCA2 [5.3%]) 
• 2% of men with early-onset PCa harbour germline mutations in the BRCA2 gene 
• BRCA2 germline alteration is an independent predictor of metastases and worse PCa-specific survival [35,42]
RR: 6.3 for metastatic
• higher rates of lethal PCa among mutation carriers 
• up to 12% of men with metastatic PCa harbour germline mutations in 16 genes (including ATM [1.6%]) 
• up to 12% of men with metastatic PCa harbour germline mutations in 16 genes (including CHEK2 [1.9%]) 
• higher rates of lethal PCa among mutation carriers 
• up to 12% of men with metastatic PCa harbour germline mutations in 16 genes (including BRCA1 [0.9%]) 
• significantly higher PSA at diagnosis, higher Gleason score and higher incidence of positive surgical margins in the radical prostatectomy specimen than non-carriers 
RR: 3.7 
• Mutations in MMR genes are responsible for Lynch syndrome 
• MSH2 mutation carriers are more likely to develop PCa than other MMR gene mutation carriers 
BRCA2 = breast cancer gene 2; ATM = ataxia telangiectasia mutated; CHEK2 = checkpoint kinase 2;BRCA1 = breast cancer gene 1; GS = Gleason score; HOXB13 = homeobox B13; MMR = mismatch repair; MLH1 = mutL homolog 1; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; OR = odds ratio; PMS2 = post-meiotic segregation increased 2; PCa = prostate cancer; RR = relative risk.
3.2.2. Risk factors
A wide variety of exogenous/environmental factors have been discussed as being associated with the risk of developing PCa or as being aetiologically important for the progression from latent to clinical PCa . Asians who immigrated to the USA have approximately half the risk of PCa when compared to their US born Asian-descendant counterparts, implying a role of environmental or dietary factors . However, currently there are no known effective preventative dietary or pharmacological interventions.
220.127.116.11. Metabolic syndrome
The single components of metabolic syndrome (MetS), hypertension (p = 0.035) and waist circumference
> 102 cm (p = 0.007), have been associated with a significantly greater risk of PCa, but in contrast, having > 3 components of MetS is associated with a reduced risk (OR: 0.70, 95% CI: 0.60–0.82) [54,55].
The association between metformin use and PCa is controversial. At population level, metformin users (but not other oral hypoglycaemic agents) were found to be at a decreased risk of PCa diagnosis compared with never users (adjusted OR: 0.84, 95% CI: 0.74–0.96) . In 540 diabetic participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, metformin use was not significantly associated with PCa and therefore not advised as a preventive measure (OR: 1.19, p = 0.50) .
A meta-analysis of 14 large prospective studies did not show any association between blood total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of developing either overall PCa or high-grade PCa . Results from the REDUCE study also did not show a preventive effect of statins on PCa risk . A meta-analysis suggested a lower risk of advanced PCa in statin users .
Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses (OR: 0.79, p = 0.01), but increased risk of high-grade PCa (OR: 1.28, p = 0.042) . This effect seems mainly explained by environmental determinants of height/body mass index (BMI) rather than genetically elevated height or BMI . A systematic review showed an association between obesity and increased PC-specific mortality .
18.104.22.168. Dietary factors
The association between a wide variety of dietary factors and PCa have been studied, but there is still a paucity of quality evidence (Table 3.2). To date, the current body of evidence will not support a causal relationship between specific (dietary and otherwise) factors and the development of PCa. Consequently, no effective preventative strategies can be suggested.
Table 3.2: Main dietary factors that have been associated with PCa
High alcohol intake, but also total abstention from alcohol has been associated with a higher risk of PCa and PCa-specific mortality . A meta-analysis shows a dose-response relationship with PCa .
Coffee consumption may be associated with a reduced risk of PCa; with a pooled RR of 0.91 for the highest category of coffee consumption .
A weak correlation between high intake of protein from dairy products and the risk of PCa was found .
No association between intake of long-chain omega-3 poly-unsaturated fatty acids and PCa was found . A relation between intake of fried foods and risk of PCa may exist .
A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes on PCa incidence has been identified in meta-analyses [68,69]. Randomised controlled trials comparing lycopene with placebo did not identify a significant decrease in the incidence of PCa .
Meta-analyses show a potential association between red meat, total meat, and processed meat consumption and PCa [71,72].
Soy (phytoestrogens [isoflavones/coumestans])
Phytoestrogen intake was significantly associated with a reduced risk of PCa in a meta-analysis . Total soy food intake has been associated with a reduced risk of PCa, but also with an increased risk of advanced disease [74,75].
A U-shaped association has been observed, with both low- and high vitamin-D concentrations being associated with an increased risk of PCa, and more strongly for high-grade disease [75,76].
An inverse association of blood, but mainly nail selenium levels (reflecting long-term exposure) with aggressive PCa have been found [77,78]. Selenium and Vitamin E supplementation were, however, found not to affect PCa incidence .
22.214.171.124. Hormonally active medication
126.96.36.199.1. 5-alpha-reductase inhibitors (5-ARIs)
Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (decreasing the risk by 25% but only for ISUP grade 1 cancer), this must be weighed against treatment-related side effects as well as the potential small increased risk of high-grade PCas, although these do not seem to impact PCa mortality [80-84] None of the available 5-ARIs have been approved by the European Medicines Agency (EMA) for chemoprevention.
Hypogonadal men receiving testosterone supplements do not have an increased risk of PCa . A pooled analysis showed that men with very low concentrations of free testosterone (lowest 10%) have a below average risk (OR: 0.77) of PCa .
188.8.131.52. Other potential risk factors
A significantly higher rate of ISUP > 2 PCa (hazard ratio [HR]: 4.04) was found in men with inflammatory bowel disease when compared with the general population . Balding was associated with a higher risk of PCa death . Gonorrhoea was significantly associated with an increased incidence of PCa (OR: 1.31, 95%
CI: 1.14–1.52) . Occupational exposure may also play a role, based on a meta-analysis which revealed that night-shift work is associated with an increased risk (2.8%, p = 0.030) of PCa . Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24, 95% CI: 1.18–1.31) and with aggressive tumour features and worse prognosis, even after quitting smoking [91,92]. A meta-analysis on Cadmium (Cd) found a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure and risk of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd levels during occupational exposure . Men positive for human papillomavirus-16 may be at increased risk . Plasma concentration of the estrogenic insecticide chlordecone is associated with an increase in the risk of PCa (OR: 1.77 for highest tertile of values above the limit of detection) .
A number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy  and self-reported acne . There are conflicting data about the use of aspirin or non-steroidal anti-inflammatory drugs and the risk of PCa and mortality [98,99].
Ultraviolet radiation exposure decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) . A review found a small but protective association of circumcision status with PCa . Higher ejaculation frequency (> 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa .
3.2.3. Summary of evidence for epidemiology and aetiology
Summary of evidence
Prostate cancer is a major health concern in men, with incidence mainly dependent on age.
Genetic factors are associated with risk of (aggressive) PCa.
A variety of dietary/exogenous/environmental factors have been associated with PCa incidence and prognosis.
In hypogonadal men, testosterone supplements do not increase the risk of PCa.
No conclusive data exist which could support specific preventive or dietary measures aimed at reducing the risk of developing PCa.