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.).

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/).

Background The presence of germline mutations plays an increasingly important role in risk assessment and treatment of prostate cancer (PrCa). Screening for high-risk mutations in subsets of patients is becoming routine. We explore the prevalence of germline genetic mutations in men with metastatic castration-resistant prostate cancer (mCRPC) recruited to the BARCODE2 trial. Methods The BARCODE2 trial is a two-part study investigating the response to carboplatin chemotherapy in mCRPC patients carrying a germline variant in a DNA repair gene (DRG). We report interim data from Part 1, in which participants are recruited for germline genetic testing using a customised next-generation sequencing panel consisting of 115 genes. Results These interim results ( N = 220) demonstrate a similar frequency of germline DRG variants in mCRPC patients compared with previously published data (15% detection rate). No significant clinical differences were identified between all carriers and non-carriers, though BRCA2/ATM carriers were found to have a shorter time to mCRPC diagnosis. Conclusions Germline pathogenic/likely pathogenic (P/LP) variants in BRCA2 and ATM genes are associated with a shorter time to progression and rarer P/LP variants in other DRG genes may play a role in mCRPC. This justifies the use of routine screening of men with advanced PrCa for germline variants and supports the need for an expanded panel test.

10500 Background: Incidence of prostate cancer (PCa) is increasing, but there is no internationally agreed population screening program. Studies using an age-based PSA approach show a high rate of false-positive results as well as over-diagnosis of indolent PCa. Genome wide association studies identify common germline variants to calculate a polygenic risk score (PRS) associated with PCa risk. The BARCODE1 study used PRS to target PCa screening to those at higher risk based on genotype. Methods: European men aged 55-69yrs were recruited via Primary Care in the UK. PRS was constructed by summing weighted risk alleles for 130 PCa risk variants using germline DNA from saliva samples via mailed kits. Men with a PRS > 90th centile were invited for PCa screening using MRI and 12-core transperineal biopsy (including MRI fusion to target additional lesions where identified) irrespective of PSA result. Results: Invitation letters were sent to 40,292 men. 8,953 (22%) expressed an interest; 8,014 were eligible and sent a saliva kit. 6,644 consented; 6,393 were genotyped; 251 failed QC. A total of 6,142 participants had PRS calculated: 745 (12.1%) had a PRS > 90th centile and were invited to screening. 558/745 participants attended screening (121 declined, 66 excluded on health grounds). 551 underwent MRI and 468 had prostate biopsy resulting in 187 (40.0%) diagnoses of PCa, overall PCa detection rate 2.8%. Mean age at diagnosis 64.1yrs (range 57-73; median 64). Using NCCN criteria (2023) 103/187 (55.1%) of cancers were Intermediate or High Risk; 40/187 (21.4%) were Intermediate Unfavourable/High/Very High Risk. 119/187 (63.6%) men had a PSA <3.0ug/L; PPV of biopsy for PSA > 3.0ug/L was 49.6%. PPV of MRI (presence of PI-RADS 3-5 lesion) 60.4%. PPV of PRS alone 40%. 103/187 (55.1%) had Gleason >7; compared with 360/1014 (35.5%) p < 0.001 in the PSA directed ERSPC study. Conclusions: A population PCa screening program using PRS risk-stratification enriches for clinically significant PCa requiring treatment. It detects a high proportion of clinically significant disease compared with PSA or MRI based screening programs and MRI missed a significant proportion (17-67%) of cancers found on biopsy. This is the first study to assess if this approach will be useful in population screening programs. Clinical trial information: NCT03857477 . [Table: see text]

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.)

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.

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: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry. Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 x 10-4). Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high -risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.& COPY; 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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.

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.

Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression.Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors asso-ciated with such progression.Design, setting, and participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) data -set.Outcome measurements and statistical analysis: A total of 15, 822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling.Results and limitations: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark"gene sets were consistently asso-ciated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset.Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort -independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management.Patient summary: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportu-nities to identify patients who might need additional treatments earlier.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

Objectives To assess the feasibility and uptake of a community‐based prostate cancer (PCa) screening programme selecting men according to their genetic risk of PCa. To assess the uptake of PCa screening investigations by men invited for screening. The uptake of the pilot study would guide the opening of the larger BARCODE1 study recruiting 5000 men. Subjects and Methods Healthy males aged 55–69 years were invited to participate via their general practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using a study specific assay. Genetic risk was based on genotyping 130 germline PCa risk single nucleotide polymorphisms (SNPs). A polygenic risk score (PRS) was calculated for each participant using the sum of weighted alleles for 130 SNPs. Study participants with a PRS lying above the 90th centile value were invited for PCa screening by prostate magnetic resonance imaging (MRI) and biopsy. Results Invitation letters were sent to 1434 men. The overall study uptake was 26% (375/1436) and 87% of responders were eligible for study entry. DNA genotyping data were available for 297 men and 25 were invited for screening. After exclusions due to medical comorbidity/invitations declined, 18 of 25 men (72%) underwent MRI and biopsy of the prostate. There were seven diagnoses of PCa (38.9%). All cancers were low‐risk and were managed with active surveillance. Conclusion The BARCODE1 Pilot has shown this community study in the UK to be feasible, with an overall uptake of 26%. The main BARCODE1 study is now open and will recruit 5000 men. The results of BARCODE1 will be important in defining the role of genetic profiling in targeted PCa population screening. Patient Summary What is the paper about? Very few prostate cancer screening programmes currently exist anywhere in the world. Our pilot study investigated if men in the UK would find it acceptable to have a genetic test based on a saliva sample to examine their risk of prostate cancer development. This test would guide whether men are offered prostate cancer screening tests. What does it mean for patients? We found that the study design was acceptable: 26% of men invited to take part agreed to have the test. The majority of men who were found to have an increased genetic risk of prostate cancer underwent further tests offered (prostate MRI scan and biopsy). We have now expanded the study to enrol 5000 men. The BARCODE1 study will be important in examining whether this approach could be used for large‐scale population prostate cancer screening.

BACKGROUND:Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE:To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS:We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS:PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS:Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY:In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

Abstract Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across racial and ethnic populations. The inadequate representation of diverse populations in current genome-wide association studies (GWAS) limits the translational potential of findings to the world's populations and could result in biased risk prediction, further exacerbating health disparities. To improve our understanding of genetic risk of PCa, we conducted the largest multiethnic PCa GWAS meta-analysis to date with 107,247 cases and 127,006 controls from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, including 85,554 cases and 91,972 controls of European ancestry, 10,368 cases and 10,986 controls of African ancestry, 8,611 cases and 18,809 controls of Asian ancestry, and 2,714 cases and 5,239 controls of Hispanic ethnicity. We identified 269 genetic risk variants independently associated with PCa risk, 86 of which were novel. Of the 183 previously reported prostate cancer risk variants, we identified stronger markers of risk for 62 variants using fine-mapping. To understand the aggregate effect of the 269 variants, we constructed a genetic risk score (GRS) using the multiethnic weights of the risk variants. Compared to men in the average 40-60% GRS category, the estimated OR for men in the top GRS decile (90-100%) was 5.06 [95% CI 4.84-5.29] for men of European ancestry, 3.74 [95% CI 3.36-4.17] for men of African ancestry, 4.47 [95% CI 3.52-5.68] for men of Asian ancestry, and 4.15 [95% CI 3.33-5.17] for Hispanic men. Men of African ancestry were estimated to have a 2.18-times higher mean GRS [95% CI 2.14-2.22], and men of Asian ancestry 0.73-times lower [95% CI 0.71-0.76], than men of European ancestry. Age significantly modified the GRS association with PCa risk, such that in men of European ancestry, the top decile GRS category was associated with an OR of 6.71 [95 % CI 5.99-7.52] for men ages 55 years or younger and 4.39 [95% CI 4.19-4.60] for men older than 55 years. Similarly, in men of African ancestry, the top GRS decile category was associated with an OR of 4.70 [95 % CI 3.65-6.07] for men ages 55 years or younger and 3.37 [95% CI 2.99-3.80] for men older than 55 years. We found that 51% of aggressive cases of European ancestry and 45% of aggressive cases of African ancestry were within the top 20% of the GRS. The lifetime absolute risk of PCa for men in the top decile of the GRS reached 38% for both African Americans [95% CI 36-41%] and Whites [95% CI 37-39%], 31% [95% CI 27-36%] for Hispanics and 26% [95% CI 22-30%] for Asians. For comparison, we constructed a genome-wide GRS, including the 269 variants and variants associated with PCa with P<1.0 × 10−5. ORs calculated with genome-wide GRS were similar and had nearly identical discriminative ability as the 269 GRS in independent samples of 6,852 cases and 193,117 controls of European ancestry and 1,586 cases and 1,047 controls of African ancestry. This suggests that a genome-wide GRS may not have improved ability to predict PCa risk compared to the 269 GRS. To understand the biological mechanisms impacted by genetic risk of PCa, we conducted integrative analyses of the GRS and serum metabolomics in 611 African ancestry men from the Multiethnic Cohort. We found that a higher GRS was associated with lower sphingolipid levels (beta=-0.08, P=3.1 × 10−4), lower androgenic steroids (beta=-0.06, P=0.003), and higher sarcosine levels (beta=0.11, P=0.002). Further, using a latent clustering approach, we found that these metabolites in conjunction with the GRS contributed to the clustering of men with low-risk, intermediate-risk, and high-risk of PCa. These findings support the role of germline variation contributing to racial and ethnic disparities in PCa risk, with the GRS offering an approach for personalized risk prediction across populations and informing the biological mechanisms underlying PCa risk. Citation Format: Burcu F. Darst, Lilit Moss, Edward J. Saunders, Nicholas Mancuso, Xin Sheng, Alisha Chou, Tokhir Dadaev, Sonja I. Berndt, Stephen K. Van Den Eeden, Stephen J. Chanock, Michael B. Cook, Tracy M. Layne, Demetrius Albanes, Hidewaki Nakagawa, John S. Witte, Practical Consortium, Rosalind A. Eeles, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multiethnic prostate cancer GWAS meta-analysis identifies novel variants, improves genetic risk prediction across populations, and informs biological mechanisms of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG03.

Abstract Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across racial and ethnic populations. The inadequate representation of diverse populations in current genome-wide association studies (GWAS) limits the translational potential of findings to the world’s populations and could result in biased risk prediction, further exacerbating health disparities. To improve our understanding of genetic risk of PCa, we conducted a multiethnic meta-analysis of PCa GWAS using 107,247 cases and 127,006 controls from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, including 85,554 cases and 91,972 controls of European ancestry, 10,368 cases and 10,986 controls of African ancestry, 8,611 cases and 18,809 controls of Asian ancestry, and 2,714 cases and 5,239 controls of Hispanic ancestry. We identified 269 genetic risk variants independently associated with PCa risk, 86 of which were novel. To understand the aggregate effect of the 269 variants, we constructed a genetic risk score (GRS) using the multiethnic weights of the risk variants. Compared to men in the average 40-60% GRS category, the estimated OR for men in the top GRS decile (90-100%) was 5.06 [95% CI 4.84-5.29] for men of European ancestry, 3.74 [95% CI 3.36-4.17] for men of African ancestry, 4.47 [95% CI 3.52-5.68] for men of Asian ancestry, and 4.15 [95% CI 3.33-5.17] for men of Hispanic ancestry. Men of African ancestry were estimated to have a 2.18-times higher mean GRS [95% CI 2.14-2.22], and men of Asian ancestry 0.73-times lower [95% CI 0.71- 0.76], than men of European ancestry. Age significantly modified the GRS association with PCa risk, such that in men of European ancestry, the top decile GRS category was associated with an OR of 6.71 [95 % CI 5.99-7.52] for men ages 55 years or younger and 4.39 [95% CI 4.19-4.60] for men older than 55 years. Similarly, in men of African ancestry, the top decile GRS category was associated with an OR of 4.70 [95% CI 3.65-6.07] for men ages 55 years or younger and 3.37 [95% CI 2.99-3.80] for men older than 55 years. We found that 51% of aggressive cases of European ancestry and 45% of aggressive cases of African ancestry were within the top 20% of the GRS. The lifetime absolute risk of PCa for men in the top decile of the GRS reached 38% for both African Americans [95% CI 36-41%] and Whites [95% CI 37-39%], 31% [95% CI 27-36%] for Hispanics and 26% [95% CI 22-30%] for Asians. For comparison, we constructed a genome-wide GRS, including the 269 variants and variants associated with PCa with P<1.0 × 10-5. ORs calculated with genome-wide GRS were similar and had nearly identical discriminative ability as the 269 GRS in independent samples of 6,852 cases and 193,117 controls of European ancestry and 1,586 cases and 1,047 controls of African ancestry. These findings support the role of germline variation contributing to racial and ethnic disparities in PCa risk, with the GRS offering an approach for personalized risk prediction across populations. Citation Format: David V. Conti, Burcu F. Darst, Lilit Moss, Edward J. Saunders, Xin Sheng, Alisha Chou, Tokhir Dadaev, Sonja I. Berndt, Stephen K. Van Den Eeden, Stephen J. Chanock, Michael B. Cook, Hidewaki Nakagawa, John S. Witte, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman. Multiethnic GWAS meta-analysis identifies novel variants and informs genetic risk prediction for prostate cancer across populations [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-146.