BACKGROUND AND OBJECTIVE:BRCA1 and BRCA2 pathogenic germline variants (PGVs) are associated with higher risk of prostate cancer (PC). The IMPACT study evaluated the utility of targeted prostate-specific antigen (PSA) screening in BRCA1/BRCA2 PGV carriers. Here we report outcomes after five rounds of PSA screening in IMPACT. METHODS:Between 2005 and 2015, 3063 participants aged 40-69 yr (median 54 yr) were recruited from 65 centres in 20 countries in two cohorts: (1) BRCA1/BRCA2 PGV carriers (915 BRCA1, 901 BRCA2); and (2) age-matched noncarriers for a familial PGV (727 BRCA1 and 520 BRCA2 noncarriers). Annual PSA screening was performed, with PSA >3.0 ng/ml used as the indication for prostate biopsy. Our aim was to identify differences by PGV status in (1) the incidence of PC and of clinically significant PC (csPC; grade group ≥2) and (2) tumour stage and characteristics after five screening rounds. KEY FINDINGS AND LIMITATIONS:There was no statistically significant difference in PC incidence between BRCA1/BRCA2 PGV carriers and noncarriers. csPC incidence was significantly higher for BRCA2 PGV carriers than for noncarriers (3.1% vs 1.3%; p = 0.04). Among men with PC, the proportion of tumours with National Comprehensive Cancer Network intermediate unfavourable/high risk was higher in the BRCA1/BRCA2 PGV groups versus the corresponding group without PGVs (BRCA2: 65% vs 32%, p = 0.029; BRCA1: 56% vs 18%, p = 0.0017). There were no T4 or metastatic PC cases. Pathology after radical prostatectomy revealed tumour upgrading for 7/23 (26%) BRCA1 PGV carriers and 10/34 (26%) BRCA2 PGV carriers, with no tumour upgrading for men without PGVs. Study limitations include the biopsy compliance rate and changes in PC diagnostic pathways since 2005. CONCLUSIONS AND CLINICAL IMPLICATIONS:Annual PSA screening in BRCA2 PGV carriers confirmed a higher incidence of csPC and detection of clinically relevant tumours in comparison to noncarriers. For the first time, we confirm that PSA screening in BRCA1 PGV carriers results in early detection of NCCN IR-U/HR PC. Systematic PSA screening is recommended for BRCA2 PGV carriers and should be considered for BRCA1 PGV carriers.

Background:Risk stratification for prostate cancer (PCa) progression or aggressiveness is often based on clinicopathologic features, some of which may be influenced by genetic factors. We developed a novel, germline polygenic risk score (PRSagg) to predict likelihood of developing aggressive PCa. Methods:PRSagg was developed using data from 38,688 patients with PCa (case-only analysis) from the Million Veteran Program (MVP) through a genome-wide search for variants associated with PCa grade group at diagnosis. We tested associations of PRSagg with grade group using the entire MVP dataset using the .632 bootstrap method. In an MVP cohort with localized PCa that was initially monitored without treatment, we tested PRSagg for association with unfavorable outcomes (subsequent development of grade group 4-5, metastasis, and/or biochemical recurrence after definitive treatment). We performed external validation in data from patients in the PRACTICAL Consortium (n=45,214) and from participants in the ProtecT randomized trial who underwent active monitoring (n=316). Odds ratios (ORs) were calculated per standard deviation (SD) increase with 95% confidence intervals, while adjusting for age, genetic ancestry, a previously developed polygenic score for risk of PCa (PHS601), and a polygenic score for benign elevated prostate-specific antigen (PRSPSA). For the outcome of metastasis, we additionally adjusted for PSA at diagnosis. Results:In the MVP training dataset, PRSagg (172 variants) was associated with higher grade group at diagnosis (OR = 1.53 [1.51-1.56]) and with increased risk of unfavorable outcomes during monitoring (OR = 1.13 [1.09-1.18]). These findings were confirmed in the external datasets. PRSagg was associated with greater odds of higher grade group at diagnosis (OR = 1.09 [1.061.11]). Among ProtecT participants undergoing active monitoring, PRSagg was associated with higher risk of metastasis (OR = 2.15 [1.02-3.88]). Among MVP participants with high polygenic risk of developing any PCa, the risk of aggressive disease was highest in men with high PRSagg and low genetic risk of PSA elevation. Conclusions:Among men who develop PCa, a weighted sum of common germline variants (PRSagg) is independently associated with PCa aggressiveness. These findings may inform future study of germline influence on tumor evolution and risk-stratified intensity of active surveillance.

Use of polygenic risk scores (PRS) as a risk-stratification tool in cancer screening is an area of increasing interest. The BARCODE1 study is an observational prostate cancer screening study, investigating the use of PRS to risk-stratify people by risk of prostate cancer, with those identified as higher risk invited for prostate cancer screening. Participants of BARCODE1 were invited to take part in a psychosocial sub-study aiming to explore the effect of receiving a polygenic risk score on psychological health, family risk communication and impact on health behaviours. 1300 participants of the BARCODE1 study were invited to complete questionnaires before and after receiving the results of their PRS. A sub-group were invited to participate in one-to-one in-depth semi-structured interviews, conducted in-person, by telephone or video-call. Interviews were audio recorded and transcribed verbatim. Data were analysed using Reflexive Thematic Analysis and the results are reported here. Eighteen participants were interviewed and four themes identified; (a) mutual benefit, (b) emotional impact, (c) risk communication and (d) stoical attitudes to health. Participants reported minimal short-term impact on psychosocial health reported following receipt of a PRS. All participants communicated their genetic risk with their spouse/partner; however, some chose not to inform their children. Participants described themselves as having typical ‘male’ stoical responses to managing their health and that they did not feel the PRS results had an impact on their health behaviours. Providing an individualised PRS informing future risk of prostate cancer was well received. Overall, participants did not report being psychologically, socially or emotionally affected by receiving this genomic risk information. For those identified as being at higher risk it is important that there is access to healthcare professionals who are competent in discussing the meaning of the results. ClinicalTrials.gov NCT03857477, registered 26th Feb 2019.

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

Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome–exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102 . Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

Abstract Background Prostate cancer (PCa) is heterogeneous, making risk stratification essential for clinical care. Although polygenic risk scores (PRSs) with main effects of single-nucleotide polymorphisms (SNPs) can help identify individuals at high risk before biological and clinical onset, a PRS for predicting PCa aggressiveness remains underdeveloped. The KLK3 , which encodes prostate-specific antigen (PSA), is linked to PCa aggressiveness. Recent findings on KLK3 SNP-SNP interactions show promise for predicting PCa aggressiveness. The objective of this study is to develop a PRS (PRS-KLK3int) by examining KLK3 SNP-SNP interaction pairs. Methods The PRS-KLK3int was developed based on a discovery set (10,836 PCa patients) and two validation sets with 14,348 and 16,584 patients of European ancestry. A total of 3145 SNP pairs and two published PRSs were evaluated. Results This study developed a PRS-KLK3int with 284 SNPs, combining an existing PRS with 270 SNPs and 12 SNP-SNP interaction pairs with 15 SNPs (one overlapped). All these 12 pairs were involved with at least one SNP from KLK3 . The PRS-KLK3int outperformed two existing PRSs in predicting PCa aggressiveness (p-values: 3.5×10 −18 , 9×10 −14 , and 1.7×10 −20 for the three sets). It effectively distinguished high-risk from low-risk groups across all datasets. The top 1% high-risk group had a higher prevalence of PCa aggressiveness than the middle 50% group (45.5% vs. 25.9%, OR = 2.38, p = 2.2×10 −5 ) in the discovery set, and similar results were observed in validation sets (OR = 2.56, p = 4.3×10 −6 ; OR = 2.07, p = 2.1×10 −5 ). Conclusions These findings support PRS-KLK3int as a valuable tool for PCa severity stratification, especially in identifying extremely high-risk PCa patients.

IntroductionProstate cancer is the second most common cancer worldwide, and there is no national prostate cancer screening programme in the United Kingdom. Men of African ancestry are twice as likely to be diagnosed as men of European ancestry and are diagnosed at a younger age. Despite this, Black men are under-represented in seeking advice about prostate cancer symptoms, screening and genetic research. There is increasing research focused on targeted prostate cancer screening, using genetic testing to guide screening by identifying those at highest risk, but this could only be considered if people of all ethnicities would accept this approach. It is vital to diagnose prostate cancer early, when it is curable. We wanted to identify the barriers to engagement with prostate cancer genetic research to increase participation from those at highest risk.MethodsWe conducted two community discussion groups, each attended by 30-35 Black men and their families. We conducted interviews with three Black community champions who have a lived experience of prostate cancer. Thematic analysis was performed on the transcripts. We used a participatory approach to develop our themes with members of the community, two of whom are co-authors on this paper.ResultsThemes were grouped as barriers or facilitators to engagement with prostate cancer genetic risk services. Barriers included GP reluctance to perform prostate-specific antigen (PSA) testing, cultural inhibition around discussing prostate cancer and family history, fear of rectal examination, fear of cancer diagnosis and lack of trust in the healthcare system, no awareness about the role of genetics in prostate cancer risk assessment, negative connotations of genetic testing (e.g., genetic modification) and genetic data being used inappropriately. Facilitators were family and community support, the sharing of experiences, good communication with doctors, raised prostate cancer awareness, genetic risk assessment to guide the need for screening and facilitate early diagnosis, improving future outcomes for prostate cancer in the Black community through engaging with genetic research and assurance that there are regulations in place to protect genetic and personal data with guidance around when genetic results must be disclosed.ConclusionsUnderstanding barriers and facilitators can guide recommendations for health services to improve access and uptake within the Black community and improve representation in genetic research. Better representation will support improvements in cancer outcomes and understanding of the genetic risk of prostate cancer in the Black community.Patient or Public ContributionWe initially attended community prostate cancer awareness events to speak to members of the community. We established trusted and two-way relationships with Black 'community champions' who lead support groups in the Black community and often have a lived experience of prostate cancer. We were invited to attend their support groups to deliver awareness talks and address concerns about prostate cancer risk and screening. We then conducted discussion groups and collected data. Our analysis was conducted in partnership with our community champions. Our findings are described in this paper, with their co-authorship. We have also disseminated our findings in a co-produced newsletter to feed back our findings to the community members, who gave us their time. We have also shared information at a stakeholder day, attended by 65 individuals from the community, where we also planned future work. We have reimbursed participants for their time, which is in line with NIHR guidance. As described above, patient and public involvement has been the guiding principle throughout this project.

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant disorder that increases the risk of various types of cancer. It is primarily caused by inherited mutations in the TP53 gene. While the tumor suppressor function of p53 is well established, its role in embryonic development, particularly in the formation of the kidney and urinary tract, remains poorly understood. Moreover, its contribution to human congenital anomalies has not been clearly defined. Here, we report that pathogenic TP53 variants can lead to congenital anomalies of the kidney and urinary tract (CAKUT), as well as genital defects (GD), in individuals with LFS. Among 28 unrelated TP53 mutation carriers, 28% (8/28) exhibited CAKUT and/or GD, with a higher frequency observed in individuals carrying structurally disruptive or dominant-negative mutations. We focused on two clinically observed variants: R242W, which destabilizes protein structure, and R282W, a dominant-negative hotspot mutation. AlphaFold modeling showed that both variants cluster within the DNA-binding domain and are predicted to disrupt tetramer formation. In Xenopus laevis, tp53 is expressed in developing nephric structures, consistent with findings from mouse models of nephrogenesis. Expression of either mutant TP53 mRNA in Xenopus embryos disrupted kidney morphogenesis in vivo , supporting a developmental loss-of-function effect. These findings indicate that pathogenic TP53 variants contribute to renal and urogenital defects in LFS. They reveal a previously unrecognized developmental role for p53 and expand the phenotypic spectrum associated with this cancer predisposition syndrome.

Background/Objectives: Prostate cancer is the most common cancer among men globally and a leading cause of cancer-related death. Germline genetic evaluation is increasingly recognized as essential for men with high-risk features such as a strong family history or advanced disease. Methods: Comprehensive genetic risk assessment should integrate three components: family history (FH), rare pathogenic mutations (RPMs), and polygenic risk scores (PRS). RPMs in DNA repair genes (e.g., BRCA2, CHEK2, ATM) can inform screening, prognosis, and treatment strategies, particularly for metastatic or aggressive disease. PRS, derived from common genetic variants, provides a personalized and independent measure of prostate cancer risk and may guide decisions on screening intensity and timing. Results: Although PRS cannot yet differentiate between indolent and aggressive cancer, it has the potential to stratify men into low and high-risk categories more effectively than FH or RPMs alone. Knowledge of specific RPMs can influence treatment decisions in clinically advanced prostate cancer. Challenges in clinical implementation include limited provider awareness, underutilization of genetic counseling, and lack of diversity in genomic datasets, which can lead to misdiagnoses. Emerging technologies and digital tools are being developed to streamline genetic testing and counseling. Population-level strategies and tailored screening protocols based on genetic risk are under active investigation. Conclusions: While early evidence suggests high satisfaction with genetic testing among patients, further studies in diverse populations are needed. Integration of germline genetic information into prostate cancer management offers promising avenues for personalized screening, surveillance, and treatment, ultimately aiming to reduce morbidity and mortality.

PURPOSE:Stereotactic body radiation therapy (SBRT) is increasingly used for oligometastatic prostate cancer, although most published series include mixed histologies and only a few patients achieve long-term disease-free survival. This retrospective study presents one of the largest prostate-only cohorts, aiming to identify who benefits most from SBRT. METHODS AND MATERIALS:From 2011 to 2023, 234 patients with ≤3 hormone-sensitive metachronous prostate cancer oligometastases were treated with SBRT at the Royal Marsden Hospital, London, and Sutton, UK. Concurrent androgen deprivation therapy (ADT) was allowed by clinician discretion. Treatment and outcome data were collected to assess the association between covariates and radiological progression-free survival (rPFS), ADT-free survival, and prostate cancer-specific survival (PCSS). RESULTS:In total, 308 lesions were treated in 234 patients. After a median follow-up of 56.5 months, median rPFS was 22 months and ADT-free survival was 42 months. The 5-year rPFS, ADT-free survival, and PCSS were 22.9%, 42.3%, and 96.4%, respectively. Concurrent ADT was used in 140 patients (59.8%). Prostate-specific antigen doubling time ≤ 3 months was a significant predictor for shorter rPFS [hazard ratio (95% CI) 1.52 (1.07-2.16), P = .001], and concurrent ADT use improved rPFS [0.52 (0.37-0.73), P < .001]. Nodal disease at primary presentation [2.08 (1.10-3.92), P = .023] and greater than 1 oligometastases [1.88 (1.25-2.82), P = .002] were inversely associated with ADT-free survival. Concurrent ADT use [0.40 (0.27-0.58), P < .001] improved ADT-free survival. Concurrent ADT use with SBRT did not improve eugonadal rPFS and eugonadal ADT-free survival. Patients diagnosed with oligometastases using baseline prostate-specific membrane antigen positron emission tomography/computed tomography had longer median ADT-free survival than those diagnosed with "other" imaging methods (52 vs 32 months, P = .041). For PCSS, more than 1 oligometastasis [6.08 (1.20-30.78), P = .029] and nodal disease at primary presentation [6.48 (1.16-36.15), P = .033] were associated with worse survival [5.95 (1.02-34.9), P = .048]. CONCLUSIONS:We present one of the largest SBRT case series specific to hormone-sensitive metachronous oligometastatic prostate cancer. After 5 years, 22.9% remained radiologically recurrence free and 42.3% remained ADT-free.

Background:Studies of germline variants in prostate cancer (PCa) have largely focused on their connections to cancer predisposition. However, an understanding of how heritable factors contribute to cancer progression and metastasis remain limited. Objective:To identify low frequency to rare germline nonsynonymous variants associated with increased risk for metastatic PCa (mPCa), while providing functional validation. Design:We assembled an extreme phenotype cohort (EPC) of 52 patients diagnosed with predominantly high-grade (Gleason Score (GS) ≥ 8) PCa and > 7 years of follow-up for which localized treatment naïve tumor tissues were available. In half of the cases, the tumor had metastasized to bone, providing an even distribution of bone mPCa and non mPCa cases. Tumor and matched distant benign DNA samples were exome sequenced and analyzed for germline variants with population-wide minor allelic frequencies ≤ 2%. Findings were validated using two independent PCa germline cohorts, including a closely matched Australian study biased to aggressive disease (n = 53) and Pan Prostate Cancer Group (PPCG, n = 976). Two mPCa-promoting candidate variants in KDM6B and BRCA2 were engineered into cell lines and functionalized. Results:Germline nonsynonymous rare variants (gnsRVs) identified in 25 DNA Damage Repair (DDR) genes were significantly enriched in the mPCa patients (p=4.57e-06). Conversely, the prevalence of synonymous variants at minor allele frequencies of ≤ 2% were similar between the mPCa and non mPCa patients. The predictive power of variants in 53 non-DDR genes was validated in the Australian cohort (p=0.028) and correlated with high-risk PCa in PPCG (p=0.03). KDM6B K973Q showed functional significance despite being annotated as benign in ClinVar, while BRCA2 I1962T showed sensitivity to Olaparib. In total, six EPC variants related to DNA repair or epigenetics were found to alter enzymatic activity. Conclusions:EPCs coupled with low frequency/rare variant analyses may advance understanding of interactions between the germline and tumor in PCa. We identified a series of germline variants that were enriched among mPCa patients. Moreover, we showed that one of these variants confers a metastatic phenotype. Our findings suggest that germline testing at diagnosis may improve treatment stratification in PCa. Patient summary:The presence of specific genetic variants among men with PCa may elevate the risk of mPCa once PCa develops. Knowledge of the variant burden at time of diagnosis may enable accurate stratification of some patients for aggressive therapeutic interventions.

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.).

OBJECTIVES:To determine mean/median serum total prostate-specific antigen (PSA) levels in transgender women and non-binary people with prostates (TWNBPP) who have received gender-affirming hormone therapy (GAHT) or an orchidectomy. The secondary objective was to identify other quantitative information that influences PSA levels in this population. METHODS:Systematic review of existing publications from primary studies published in English, excluding case reports and guidelines. INCLUDED STUDIES:TWNBPP who have received GAHT/post-orchidectomy, without a diagnosis of prostate pathology, with recorded serum PSA levels. MEDLINE and Embase databases were searched, up to July 2024. RESULTS:Four papers met the inclusion criteria, with 290 participants. Two papers measured the mean PSA level after 4 and 12 months of GAHT (mean [range] age 30 [18-45] years). A third paper measured the mean PSA level after a median of 9 years of GAHT (mean [range] age 40.1 [19-67] years). The fourth study measured 852 PSA levels in 210 participants receiving oestradiol therapy, over a 23-year period (mean [range] age 60 [40-79] years). The mean and median PSA levels ranged from 0.020 to 0.525 ng/mL. Meta-analysis of these data was unfeasible, due to low quantity, comparability, and quality of the studies. CONCLUSIONS:Existing data for serum PSA reference intervals for TWNBPP without prostate pathology were from four studies and cannot be used to make clinical recommendations. The evidence indicates that GAHT in TWNBPP lowers PSA levels from baseline, below expected levels for age-matched cisgender controls. Not all TWNBPP over the age of 40 years should be offered PSA testing; however, those with a genetic predisposition, family history, or symptoms of prostate cancer, may request or be offered a PSA test. There are currently no clinical PSA thresholds to guide interpretation of PSA levels in TWNBPP when being evaluated for suspected prostate cancer or for those seeking PSA testing.

Prostate cancer (PCa) germline testing, while gaining momentum, is ancestry restrictive and African exclusive. Through whole genome sequencing for 217 African ancestral cases (186 southern African, 31 Pan representative), we identify 172 potentially pathogenic variants in 78 DNA damage repair or PCa related genes. Prevalence for reported (13/217, 5.99%) and cumulative predicted (24/217, 11.06%) variants of significance (11 genes) falls below that reported for non-Africans. Conversely, BRCA1, HOXB13, CDK12, MLH1, MSH2, and BRIP1 remain unimpacted. Through pathogenic ranking based on variant frequency and functionality, clinical presentation and tumour-matched biallelic inactivation, top-ranked candidates include PREX2, POLE, FAT1, BRCA2, POLQ, LRP1B and ATM. Besides notable impact of DNA polymerases, including POLG, Fanconi anaemia genes include FANCD2, FANCA, FANCG, ERCC4, FANCE and FANCI, while DNA mismatch repair genes MSH3 and PMS1 outranked known namesakes MSH6 and PMS2. This study provides insights into the spectrum of African-relevant potentially pathogenic PCa variants, highlighting much-needed gene candidates for ancestry-inclusive germline testing.

Oncomicrobes are estimated to cause 15% of cancers worldwide. When cancer whole-genome sequencing (WGS) data are collected, the microbes present are also sequenced, allowing the investigation of potential etiological and clinical associations. Interrogating the microbial community for 8908 patients encompassing 22 cancer types from the Genomics England WGS dataset revealed that only colorectal tumors exhibited unmistakably distinct microbial communities that can reliably be used to distinguish anatomical site [positive predictive value (PPV) = 0.95]. This pattern was validated in two independent datasets. Potential clinical relevance uncovered by our analyses included accurate detection of alphapapillomaviruses [human papillomavirus (HPV)] in oral cancers, when compared with current clinical standards, and the detection of rare, highly pathogenic viruses such as human T-lymphotropic virus-1. Biomarker investigations demonstrated statistically significant associations (P < 0.05) between a subset of anaerobic bacteria and survival in certain subtypes of sarcoma. Our results contradict previous claims that each cancer type has a distinct microbiological signature but highlight the potential value of microbial analysis for certain cancers as WGS of tumor samples becomes common in the clinic.

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%.

234 Background: The HSD3B1 gene encodes for the 3βHSD1 enzyme which regulates the rate-limiting step in potent androgen synthesis from non-gonadal precursors. The missense-encoding adrenal-permissive form of HSD3B1 generates a hyperactive 3βHSD1 enzyme compared to the adrenal-restrictive form. We aimed to test associations with OS for HSD3B1 genotyped patients randomized 1:1 to ADT vs. ADT+ENZ+AAP in the STAMPEDE platform protocol. Methods: HSD3B1 genotype was performed in germline DNA using a validated melting assay. We included patients who donated saliva or white blood cells for translational studies and were not planned for “triplet therapy with” docetaxel. Association between HSD3B1 gene and overall survival was estimated using Cox survival models adjusted for randomised group, age at randomization, WHO performance status, regular aspirin or NSAID use, planned radiotherapy and metastatic disease status. Predictive effect was estimated with the addition of an interaction term. We pre-specified M1 low volume as of primary interest given prior associations in the CHAARTED trial. Results: Germline HSD3B1 genotype was obtained for 259 men in the ADT arm and 335 men in the ADT+ENZ+AAP arm (594 total). 319 (54%) men were adrenal-permissive and 275 were adrenal-restrictive. Adrenal-permissive HSD3B1 was associated with shorter OS (HR, 1.32 [1.04-1.67, p=0.025]), which by pre-specified sub-group analysis was most strongly prognostic in low volume (N=185, HR 1.70 [1.12-2.59], p=0.012) versus M0 (N=248, HR 1.21 [0.74-1.96], p=0.442) or M1 high volume (N=161, HR 1.14 [0.78-1.67] p=0.490) Although, there was no evidence of an interaction between treatment arm and genotype (p=0.800, 0.231 and 0.480 for M0, M1 LV and M1 HV, respectively), the treatment effect in the M1 LV restrictive group was 0.37 [0.19, 0.71] versus 0.7 [0.41, 1.21] in the permissive group. Conclusions: Adrenal-permissive HSD3B1 inheritance is associated with increased risk of death in men starting long-term ADT ± ENZ+AAP in STAMPEDE. This result is consistent with prior analyses of the CHAARTED trial and prostatectomy cohorts. This effect is most notable in M1 LV and not overcome by addition of ENZ+AAP to ADT.

Despite advances in understanding and treating Prostate Cancer (PCa), there has been little effort to systematically map the biology distinguishing Early-(EOPCa) and Late-(LOPCa) onset PCa. Around 25% of EOPCa cases present with metastatic spread or aggressive disease with earlier metastatic development. Some available lines of therapy are extending treatment trajectories and prolonging lives. However, there remains a critical clinical need to identify new therapeutic targets for EOPCa where life expectancy necessitates safer, more targeted treatment options. To our knowledge, here we present the largest systematic analysis of molecular profiles in EOPCa versus LOPCa, employing machine-learning-enabled algorithms to identify distinguishing biology and druggable targets for each age group. Distinct stromal signatures are uncovered in EOPCa, which are used to propose therapeutic opportunities herein. Moreover, our analysis identifies 50 druggable targets, 11 of which we confirm in PCa cell line genetic/pharmacological perturbation data. These findings provide the first specific, testable hypotheses in EOPCa, offering avenues for experimental validation and potential therapeutic exploitation, and, more generally, shed light on the intricate and distinguished molecular profile of this aggressive, poorly understood disease. One Sentence Summary Machine learning-enabled algorithms were utilized to identify distinguishing biology and associated druggable targets for early-onset prostate cancers. ### Competing Interest Statement BA-L declares financial interest in Recursion Pharmaceuticals, Drug Hunter, and AstraZeneca PLC. BA-L is/has been a member of Scientific Advisory Boards and/or provided paid consultancy for the following: Astex Pharmaceuticals, AstraZeneca PLC, GSK PLC, Novo Nordisk, Sante Ventures. She is a lead on the MD Anderson Drug Discovery and Development Division which has commercial interest in target and drug discovery. She was a chair and member of the Scientific Advisory Board for Open Targets. She is chair of the Cancer Research UK Data Strategy Board and member of the CRUK Scientific Advisory Board. She is a member of the New York Genome Consortium Scientific Advisory Board. She is a member of the Board of Directors of the Leukemia and Lymphoma Society. She is Director of non-profit Chemical Probes Portal. RAE has received honoraria from GU-ASCO, Janssen, University of Chicago, Dana Farber Cancer Institute USA as a speaker. Educational honorarium from Bayer and Ipsen, member of external expert committee to Astra Zeneca UK and Member of Active Surveillance Movember Committee. She is a member of the SAB of Our Future Health. She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. PW is or has been a consultant/scientific advisory board member for Alterome Therapeutics, Astex Pharmaceuticals, Black Diamond Therapeutics, CHARM Therapeutics, CV6 Therapeutics, Cyclacel Pharmaceuticals, Epicombi.AI, Merck KGaA, Nuevolution (acquired by Amgen), Nextech Invest, and Vividion Therapeutics (acquired by Bayer AG); has received research funding from Astex Pharmaceuticals, Merck KGaA and Vivan Therapeutics; is a Director of Storm Therapeutics and Derwentwater Associates and a Science Partner at Nextech Invest; holds equity in Alterome Therapeutics, Black Diamond Therapeutics, CHARM Therapeutics, Chroma Therapeutics, Epicombi.AI, Nextech Invest, and Storm Therapeutics; and is a former employee of Zeneca Pharmaceuticals. PW is also Executive Director of the non-profit Chemical Probes Portal. BA-L, ZK-J, AL, BO, QK, SM, CM, and PW are/have been employees of the ICR, which has a Rewards to Inventors scheme and a commercial interest in the development of cancer drug targets. BA-L and STS are employees of UT MD Anderson Cancer Center which operates a reward to inventor scheme.

Background: Bacteria play a suspected role in the development of several cancer types, and associations between the presence of particular bacteria and prostate cancer have been reported. Objective: To provide improved characterisation of the prostate and urine microbiome and to investigate the prognostic potential of the bacteria present. Design, setting, and participants: Microbiome profiles were interrogated in sample col-lections of patient urine (sediment microscopy: n = 318, 16S ribosomal amplicon sequencing: n = 46; and extracellular vesicle RNA-seq: n = 40) and cancer tissue (n = 204). Outcome measurements and statistical analysis: Microbiomes were assessed using anaerobic culture, population-level 16S analysis, RNA-seq, and whole genome DNA sequencing. Results and limitations: We demonstrate an association between the presence of bacteria in urine sediments and higher D'Amico risk prostate cancer (discovery, n = 215 patients, p < 0.001; validation, n = 103, p < 0.001, v2 test for trend). Characterisation of the bacterial community led to the (1) identification of four novel bacteria (Porphyromonas sp. nov., Varibaculum sp. nov., Peptoniphilus sp. nov., and Fenollaria sp. nov.) that were frequently found in patient urine, and (2) definition of a patient sub-group associated with metastasis development (p = 0.015, log-rank test). The presence of five specific anaerobic genera, which includes three of the novel isolates, was associated with cancer risk group, in urine sediment (p = 0.045, log-rank test), urine extracellular vesicles (p = 0.039), and cancer tissue (p = 0.035), with a meta-analysis hazard ratio for disease progression of 2.60 (95% confidence interval: 1.39-4.85; p = 0.003; Cox regression). A limitation is that functional links to cancer development are not yet established. Conclusions: This study characterises prostate and urine microbiomes, and indicates that specific anaerobic bacteria genera have prognostic potential. Patient summary: In this study, we investigated the presence of bacteria in patient urine and the prostate. We identified four novel bacteria and suggest a potential prognostic utility for the microbiome in prostate cancer. (C) 2022 Published by Elsevier B.V. on behalf of European Association of Urology.