Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger’s MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] < 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p<5×10-8; MAF>0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p<2.4×10-6) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2), BRCA2 (OR=2.0, 95% CI=1.7-2.3), CHEK2 (OR=1.6, 95% CI=1.5-1.8), ATM (OR=1.6, 95% CI=1.4-1.9), FAM111A (OR=1.4, 95% CI=1.3-1.5), BIK (OR=1.4, 95% CI=1.2-1.6), SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB390.

Pathogenic germline variants in DNA damage response and repair (DDR) genes are established risk factors for prostate cancer (PrCa). Genetic testing for inherited PrCa is usually limited to small gene panels, even though common variants are recognised as harbouring a significant proportion of heritable risk. We have developed a genetic test to identify individuals with a genetic predisposition to PrCa from rare and/or common risk variants, with added potential to inform clinical management of PrCa patients, by detecting targets for personalised treatment, and gather further evidence for candidate genes. Germline genetic testing was offered to 1095 PrCa patients, as part of a research study, to inform on genetic predisposition and determine eligibility for personalised treatment options. Targeted sequencing of 117 DDR genes and HOXB13 was performed together with genotyping of 130–396 common PrCa risk variants. This test we have called PRODICT. Genetic reports were provided to participants including (A) rare variant status and (B) polygenic risk score (PRS). Pathogenic or likely pathogenic (P/LP) variants were detected in 16.7

BACKGROUND:The incidence of prostate cancer is increasing. Screening with an assay of prostate-specific antigen (PSA) has a high rate for false positive results. Genomewide association studies have identified common germline variants in persons with prostate cancer, which can be used to calculate a polygenic risk score associated with risk of prostate cancer. METHODS:We recruited persons 55 to 69 years of age from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, we derived polygenic risk scores from 130 variants known to be associated with an increased risk of prostate cancer. Participants with a polygenic risk score in the 90th percentile or higher were invited to undergo prostate cancer screening with multiparametric magnetic resonance imaging (MRI) and transperineal biopsy, irrespective of PSA level. RESULTS:Among 40,292 persons invited to participate, 8953 (22.2%) expressed interest in participating and 6393 had their polygenic risk score calculated; 745 (11.7%) had a polygenic risk score in the 90th percentile or higher and were invited to undergo screening. Of these 745 participants, 468 (62.8%) underwent MRI and prostate biopsy; prostate cancer was detected in 187 participants (40.0%). The median age at diagnosis was 64 years (range, 57 to 73). Of the 187 participants with cancer, 103 (55.1%) had prostate cancer classified as intermediate or higher risk according to the 2024 National Comprehensive Cancer Network (NCCN) criteria, so treatment was indicated; cancer would not have been detected in 74 (71.8%) of these participants according to the prostate cancer diagnostic pathway currently used in the United Kingdom (high PSA level and positive MRI results). In addition, 40 of the participants with cancer (21.4%) had disease classified as unfavorable intermediate risk or as high or very high risk according to NCCN criteria. CONCLUSIONS:In a prostate cancer screening program involving participants in the top decile of risk as determined by a polygenic risk score, the percentage found to have clinically significant disease was higher than the percentage that would have been identified with the use of PSA or MRI. (Funded by the European Research Council Seventh Framework Program and others; BARCODE1 ClinicalTrials.gov number, NCT03857477.).

Whole genome sequencing (WGS) presents an opportunity to identify asymptomatic individuals at increased risk for disease. We set up a model pathway to assess the use of WGS combined with a medical assessment in primary care. We recruited 104 participants (102 unrelated) from a private general practice for a medical assessment, WGS and panel testing. WGS analysed 566 clinically actionable genes, including moderate to high-risk monogenic traits, recessive traits and pharmaco-genes. Polygenic risk scores (PRS) were calculated for 4 cancers. Twenty-three individuals (22%) had an actionable germline variant in cancer, cardiac, lipid or thromboembolic genes. Ten of these (43%) had pathogenic variants in cancer predisposition genes, 60 (58%) participants harboured recessive genetic alterations and 43 (41%) had pharmacogenetic variants. Our findings show WGS in primary care identified actionable variants in 22% of individuals resulting in a change in clinical management. Pharmacogenomics may alter prescribing in a further 41%.

Background: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. Objective: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). Design, setting, and participants: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. Outcome measurements and statistical analysis: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score >8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. Results and limitations: We observed associations between PrCa aggressiveness and pLOF mutations in ATM , BRCA2 , MSH2 , and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 x 10 -16 ) than noncarriers. Conclusions: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. Patient summary: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa. (c) 2024 The Institute of Cancer Research. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes. The PSA (KLK3) genetic variant rs17632542 is associated with reduced prostate cancer risk and lower serum PSA levels, although the underlying reasons are unclear. Here, the authors show that this PSA variant reduced proteolytic activity and leads to smaller tumours, but also increases invasion and bone metastasis, indicating its dual risk association depending on tumour context; the variant is associated with both lower risk and poor clinical outcomes.

Importance:Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. Objective:To identify genes associated with aggressive PCa. Design, Setting, and Participants:A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Exposure:Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. Main Outcomes and Measures:The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. Results:A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. Conclusions and Relevance:The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

Supplementary Notes. This document includes description of studies that they have been used for the analysis.

Supplementary Figure 2. Absolute Risk (With no family history of prostate cancer.)

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity as a previously undescribed function mediating prostate cancer pathogenesis. The ‘Thr’ PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele had reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry ( P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

PURPOSEProstate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort.MATERIALS AND METHODSWe developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study.RESULTSThe most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years.CONCLUSIONTo our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches.

Supplementary Tables 1-8. Supplementary table 1: Total number of cases and controls in PRACTICAL III and GWAS stage 3 by population and study. Supplementary Table 2: Data information for family history and age at diagnosis/observation. Supplementary Table 3: Grade-specific and family history-specific odds ratios. Supplementary Table 4: PSA levels by genotype in controls. Supplementary Table 5: Age-specific odds ratios. Supplementary Table 6: The results of 29 pair wise interaction of 25 SNPs significant at P <0.05 (29 out of 300 interactions; Bonferroni correction 0.05/300=1.67x10-4). Supplementary Table 7: Estimated odds ratios of PRS percentiles adjusted for age at diagnosis of PrCa (five categories) in a model allowing for an interaction between PRS and Age. Supplementary Table 8: Estimated odds ratios used for estimating absolute risk.

Background: A family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis. Objective: To determine how the number, degree, and age of a PrCa patient's affected rel-atives are associated with OS and PCSS of those already diagnosed with PrCa. Design, setting, and participants: The UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16 340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). Outcome measurements and statistical analysis: The primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by cal-culating hazard ratios from Cox proportional hazard regression models, adjusting for rel-evant factors. Results and limitations: A stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all -cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75-0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases. Conclusions: Based on the investigation of the type and timing of relatives' cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS269). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS269 constructed with fine-mapping.

Objectives:The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. Methods:Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. Results:A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. Conclusions:Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit.