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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 19378 cases and 61620 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 × 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.

Available evidence supports routine implementation of germline genetic testing for many aspects of prostate cancer (PCa) decision making. The purpose of obtaining genetic testing for newly diagnosed men would be focused on identifying mutations that predispose to aggressive PCa. Based on an evidence-based review, the authors review germline rare pathogenic mutations in several genes that are significantly associated with aggressiveness, metastases, and mortality. Then recent studies of these germline mutations in predicting tumor grade reclassification among patients undergoing active surveillance are discussed. Single nucleotide polymorphisms-based polygenic risk scores in differentiating PCa aggressiveness and prognosis are reviewed.

Background Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. Objective To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. Design, setting, and participants A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. Outcome measurements and statistical analysis Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. Results and limitations Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. Conclusions Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. Patient summary Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

We aim to understand, from acquired genetic alterations in tumors, why African American (AA) men are more likely to develop aggressive prostate cancer. By analyzing somatic mutations in 39 genes using deeper next-generation sequencing with an average depth of 2,522 reads for tumor DNA and genome-wide DNA copy-number alterations (CNA) in prostate cancer in a total of 171 AA/black men and comparing with those in 860 European American (EA)/white men, we here present several novel findings. First, >35% of AA men harbor damaging mutations in APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, each with >1% of mutated copies. Second, among genes with >10% of mutated copies in tumor cells, ZMYM3 is the most frequently mutated gene in AA prostate cancer. In a patient's tumor with >96% frameshift mutations of ZMYM3, we find allelic imbalances in 10 chromosomes, including losses of five and gains of another four chromosomes, suggesting its role in maintaining genomic integrity. Third, when compared to prostate cancer in EA/white men, a higher frequency of CNAs of MYC, THADA, NEIL3, LRP1B, BUB1B, MAP3K7, BNIP3L and RB1, and a lower frequency of deletions of RYBP, TP53, and TMPRSS2-ERG are observed in AA/black men. Finally, for the above genes with higher frequency of CNAs in AA than in EA, deletion of MAP3K7, BNIP3L, NEIL3 or RB1, or gain of MYC significantly associates with both higher Gleason grade and advanced pathologic stage in AA/black men. Deletion of THADA associates with advanced pathologic stage only. Implications: A higher frequency of damaging mutation in ZMYM3 causing genomic instability along with higher frequency of altered genomic regions including deletions of MAP3K7, BNIP3L, RB1, and NEIL3, and gain of MYC appear to be distinct somatically acquired genetic alterations that may contribute to more aggressive prostate cancer in AA/black men.

The role of truncated androgen receptor splice variant-7 (AR-V7) in prostate cancer biology is an unresolved question. Is it simply a marker of resistance to 2nd-generation androgen receptor signaling inhibitors (ARSi) like abiraterone acetate (Abi) and enzalutamide (Enza) or a functional driver of lethal resistance via its ligand-independent transcriptional activity? To resolve this question, the correlation between resistance to ARSi and genetic chances and expression of full length AR (AR-FL) vs. AR-V7 were evaluated in a series of independent patient-derived xenografts (PDXs). While all PDXs lack PTEN expression, there is no consistent requirement for mutation in TP53, RB1, BRCA2, PIK3CA, or MSH2, or expression of SOX2 or ERG and ARSi resistance. Elevated expression of AR-FL alone is sufficient for Abi but not Enza resistance, even if AR-FL is gain-of-function (GOF) mutated. Enza resistance is consistently correlated with enhanced AR-V7 expression. In vitro and in vivo growth responses of Abi-/Enza-resistant LNCaP-95 cells in which CRISPR-Cas9 was used to knockout AR-FL or AR-V7 alone or in combination were evaluated. Combining these growth responses with RNAseq analysis demonstrates that both AR-FL- and AR-V7-dependent transcriptional complementation are needed for Abi/Enza resistance.

International audience; Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age

Germline HOXB13 G84E mutation has been consistently associated with prostate cancer (PCa) risk, but its association with other cancers is controversial. We systematically tested its association with the 20 most common cancer types in subjects from the UK Biobank. The G84E mutation was found in 1,545 (0.34%) of 460,224 participants of European ancestry. While mutation status did not associate with cancer risk in females, it was significantly associated with increased risk in males; odds ratio (OR) (95% confidence interval) for overall cancer diagnosis was 2.19 (1.89–2.52), P = 2.5E-19. The association remained after excluding PCa; OR = 1.4 (1.16–1.68), P = 0.003, suggesting association with other cancers. Indeed, suggestive novel associations were found for two other cancer types; rectosigmoid cancer, OR = 2.25 (1.05–4.15), P = 0.05 and non-melanoma skin cancer (NMSC), OR = 1.40 (1.12–1.74), P = 0.01. For NMSC, the association was found only in basal cell carcinoma, OR = 1.37 (1.07–1.74), P = 0.03. These findings have potential clinical utility for genetic counselling regarding HOXB13.

Background To assess the feasibility of a novel DNA-based probe panel to detect copy number alterations (CNAs) in prostate tumor DNA and its performance for predicting clinical progression. Methods A probe panel was developed and optimized to measure CNAs in trace amounts of tumor DNA (2 ng) isolated from formalin-fixed paraffin-embedded tissues. Ten genes previously associated with aggressive disease were targeted. The panel's feasibility and performance were assessed in 175 prostate cancer (PCa) patients who underwent radical prostatectomy with a median 10-year follow-up, including 42 men who developed disease progression (either metastasis and/or PCa-specific death). Association with disease progression was tested using univariable and multivariable analyses. Results The probe panel detected CNAs in all 10 genes in tumor DNA isolated from either diagnostic biopsies or surgical specimens. A four-gene model (PTEN/MYC/BRCA2/CDKN1B) had the strongest association with disease progression; 64.3% of progressors and 22.5% of non-progressors had at least one CNA in these four genes, odds ratio (OR) (95% confidence interval) = 6.21 (2.77-13.87), P = 8.48E-06. The association with disease progression remained significant after adjusting for known clinicopathological variables. Among the seven progressors of the 65 patients with clinically low-risk disease, three (42.9%) had at least one CNA in these four genes. Conclusions The probe panel can detect CNAs in trace amounts of tumor DNA from biopsies or surgical tissues at the time of diagnosis or surgery. CNAs independently predict metastatic/lethal cancer, particularly among men with clinically low-risk disease at diagnosis. If validated, this may improve current abilities to assess tumor aggressiveness.

Background Genome‐wide association studies have identified over 100 single‐nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study. Methods The sample included 1972 PrCa cases and 1919 unaffected controls. Next‐generation sequencing was used to assess pathogenic variants in 14 PrCa‐susceptibility genes and 72 validated PrCa‐associated SNPs. We constructed a population‐standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa. Results The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P

BACKGROUND: Recently, a novel HOXB13 variant (X285K) was observed in men of African descent with prostate cancer (PCa) in Martinique. Little is known about this or other variants in HOXB13 which may play a role in PCa susceptibility in African-American (AA) men. METHODS: We sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital. RESULTS: Seven non-synonymous germline variants were observed in the patient population. While six of these variants were seen only once, X285K was found in eight patients. In a case–case analysis, we find that carriers of this latter variant are at increased risk of clinically significant PCa (1.2% carrier rate in Gleason Score ≥7 PCa vs. 0% in Gleason Score

Summary Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC., Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.

INTRODUCTION AND OBJECTIVE:Germline testing for prostate cancer (PCa) is now recommended by clinical guidelines. A critical clinical utility is to predict prognosis. Ten genes involved in hereditar...

INTRODUCTION AND OBJECTIVE:Germline testing for prostate cancer (PCa) is now recommended by clinical guidelines for PCa risk assessment. Ten genes involved in hereditary cancer syndromes (ATM, BRCA...

INTRODUCTION AND OBJECTIVE:Clinical guidelines now include germline testing for prostate cancer (PCa). Currently, only 11 genes are routinely evaluated for rare pathogenic mutations (RPMs). Common ...

INTRODUCTION AND OBJECTIVE:Middle age men, especially those with modestly increased PSA levels, are at increased risk for diagnosis of prostate cancer (PCa) and/or benign prostatic hyperplasia (BPH...

The identification and characterization of alterations in prostate cancer (PCa)-predisposing genes can help to inform screening strategies in undiagnosed men and treatment options in men in both the clinically localized and in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PCa, the current role of genetics and PCa risk assessment, and how genetic risk factors affect aggressiveness and lethality of PCa.

BACKGROUND Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk-associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied. METHODS We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad-sense validity) and score values (narrow-sense validity). RESULTS A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk-associated SNPs. For broad-sense validity in the testing population, higher deciles were significantly associated with higher observed risk; Ptrend was 7.40 × 10-11 , 7.64 × 10-13 , and 7.51 × 10-10 for GRS, P + T, and LDpred, respectively. For narrow-sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively. CONCLUSIONS The performance of GRS was better than P + T and LDpred. Fewer and well-established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level.

Recent studies suggest a diet low in dietary magnesium intake or lower blood magnesium levels is linked with increased prostate cancer risk. This study investigates the race-specific link between blood magnesium and calcium levels, or dietary magnesium intake, and the diagnosis of low-grade and high-grade prostate cancer. The study included 637 prostate cancer cases and 715 biopsy-negative controls (50% black) recruited from Nashville, TN or Durham, NC. Blood was collected at the time of recruitment, and dietary intake was assessed by food frequency questionnaire. Percent genetic African ancestry was determined as a compliment to self-reported race. Blood magnesium levels and dietary magnesium intake were significantly lower in black compared to white men. However, magnesium levels or intake were not associated with risk of total prostate cancer or aggressive prostate cancer. Indeed, a higher calcium-to-magnesium diet intake was significantly protective for high-grade prostate cancer in black (OR = 0.66 (0.45, 0.96), p = 0.03) but not white (OR = 1.00 (0.79, 1.26), p = 0.99) men. In summary, there was a statistically significant difference in magnesium intake between black and white men, but the biological impact was unclear, and we did not confirm a lower prostate cancer risk associated with magnesium levels.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

Background Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention. Methods This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40–70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups. Results The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants’ reported optimism about their future health neither before nor after receiving GRS results. Conclusions Genetic risk scores that quantify an individual’s risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

International audience; 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.

BackgroundClinical studies have suggested that prostate health index (phi) outperforms prostate-specific antigen (PSA) tests in prostate cancer detection. The cost-effectiveness of phi with different cutoffs is poorly understood in the context of decision making for prostate biopsy.MethodsIn a multicenter cohort, 3,348 men with elevated total PSA (tPSA) underwent initial prostate biopsy from August 2013 to May 2019. We constructed a decision model to evaluate the incremental cost-effectiveness ratios of different phi cutoffs. Total costs and reimbursement payments were based on the fee schedule of Shanghai Basic Medical Insurance and converted into United States dollars ($). Two willingness-to-pay thresholds were estimated as one or three times the average gross domestic product per capita of China ($7,760 or $23,279, respectively).ResultsThe total costs of prostate biopsy and PSA tests were estimated at $315 and $19, respectively. The cost of phi test varied between $72 to $130 in different medical centers. Under different phi cutoffs (from 23 to 35), phi test predicted reductions of 420 (21.7%) to 972 (50.2%) in unnecessary biopsies, with a total gain of 23.77–57.58 quality adjusted life-years compared to PSA tests. All the cutoffs would be cost-effective for patients with tPSA levels of 2–10 ng/ml. Applying 27 as the cutoff was cost-effective for each tPSA range, with missing positive cases ranging from 11 (3.4%) to 33 (11.5%).ConclusionsUsing phi test was cost-effective in the decision-making process for initial prostate biopsy, especially for patients with tPSA values between 2–10 ng/ml. The phi cutoff of 27 was cost-effective regardless of tPSA ranges and should be recommended from a health-economic perspective.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

BackgroundSNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their percentile rank and disease risk in populations. However, for clinical use at the individual level, the reliability of score values is necessary considering they are directly used to calculate remaining lifetime risk.ObjectivesWe assessed the reliability of polygenic score values to estimate prostate cancer (PCa), breast cancer (BCa) and colorectal cancer (CRC) risk in three incident cohorts from the UK Biobank (n>500 000).MethodsCancer-specific Genetic Risk Score (GRS), a well-established population-standardised polygenic risk score, was calculated.ResultsA systematic bias was found between estimated risks (GRS values) and observed risks; β (95% CI) was 0.67 (0.58–0.76), 0.74 (0.65–0.84) and 0.82 (0.75–0.89), respectively, for PCa, BCa and CRC, all significantly lower than 1.00 (perfect calibration), pConclusionAssessing the calibration of polygenic risk scores is necessary and feasible to ensure their reliability prior to clinical implementation.

Dramatic progress has been made in the area of germline genetics of prostate cancer (PCa) in the past decade. Both common and rare genetic variants with effects on risk ranging from barely detectable to outright practice-changing have been identified. For men with high risk PCa, the application of genetic testing for inherited pathogenic mutations is becoming standard of care. A major question exists about which additional populations of men to test, as men at all risk levels can potentially benefit by knowing their unique genetic profile of germline susceptibility variants. This article will provide a brief overview of some current issues in understanding inherited susceptibility for PCa. Keywords: Genetic susceptibility, BRCA2, Single-nucleotide polymorphisms, Mutations, Germline genetics, Prostate cancer

Key Points Question Is family history sufficient to identify men at high risk of prostate cancer? Findings In a cohort study of 3225 men, family history alone identified 14% at high risk of prostate cancer and 86% at low or average risk; men with a positive family history of prostate cancer had a median diagnosis-free survival of 73 years, while men with a negative family history had a median diagnosis-free survival of 77 years. A combination of family history and single-nucleotide polymorphism–based genetic risk score, however, identified 30% of men at high genetic risk of prostate cancer, 52% of men at average genetic risk, and 19% of men at low genetic risk; the median diagnosis-free survival was 74 years for men at high genetic risk, 77 years for men at average genetic risk, and more than 80 years for men at low genetic risk. Meaning Combining family history and genetic risk score can better stratify inherited risk to develop personalized prostate cancer screening strategies., Importance Few studies have evaluated the association between a single-nucleotide polymorphism–based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. Objectives To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. Design, Setting, and Participants A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. Interventions A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk–associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis–free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. Conclusions and Relevance This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies., This cohort study examines the association between a single-nucleotide polymorphism (SNP)–based genetic risk score and patient age at prostate cancer diagnosis and compares the performance of the genetic risk score with that of family history in prostate cancer risk stratification.

BACKGROUND Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.

PURPOSE: Family history assigns equivalent risk to all relatives based upon the degree of relationship. Recent genetic studies have identified single nucleotide polymorphisms (SNPs) that can be used to calculate a genetic risk score (GRS) to determine prostate cancer (PCa) risk. We sought to determine whether GRS can stratify PCa risk among individuals in families considered to be at higher risk due their family history of PCa. MATERIALS AND METHODS: Family members with hereditary PCa were recruited and genotyped for 17 SNPs associated with PCa. A GRS was calculated for all subjects. Analyses compared the distribution of GRS values among affected and unaffected family members of varying relationship degrees. RESULTS: Data was available for 789 family members of probands including 552 affected and 237 unaffected relatives. Median GRSs were higher among first-degree relatives compared to second- and third-degree relatives. In addition, GRS values among affected first- and second-degree relatives were significantly higher than unaffected relatives (P = 0.042 and P = 0.016, respectively). Multivariate analysis including GRS and degree of relationship demonstrated that GRS was a significant and independent predictor of PCa (OR 1.52, 95%CI 1.15–2.01). CONCLUSION: GRS is an easy-to-interpret, objective measure that can be used to assess differences in PCa risk among family members of affected men. GRS allows for further differentiation among family members, providing better risk assessment. While prospective validation studies are required, this information can help guide relatives in regards to the time of initiation and frequency of PCa screening.

Background Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment.

Background Both common and rare genetic variants may contribute to risk of developing prostate cancer. Genome-wide association studies (GWASs) have identified ∼100 independent, common variants associated with prostate cancer risk. However, little is known about the association of rare variants (minor allele frequency [MAF]

The performance of prostate health index (phi) in predicting prostate biopsy outcomes has been well established for patients with prostate-specific antigen (PSA) values between 2 and 10 ng/mL. However, the performance of phi remains unknown in patients with PSA10 ng/mL, the vast majority in Chinese biopsy patients. We aimed to assess the ability of phi to predict prostate cancer (PCa) and high-grade disease (Gleason Score ≥7) on biopsy in a Chinese population.This is a prospective, observational, multi-center study of consecutive patients who underwent a transrectal ultrasound guided prostate biopsy at four hospitals in Shanghai, China from August 2013 to December 2014.In the cohort of 1538 patients, the detection rate of PCa was 40.2%. phi had a significantly better predictive performance for PCa than total PSA (tPSA). The areas under the receiver operating characteristic curve (AUC) were 0.90 and 0.79 for phi and tPSA, respectively, P 0.0001. A considerable proportion of patients in the cohort had PSAs10 ng/mL (N = 838, 54.5%). The detection rates of PCa were 35.9% and 57.7% in patients with tPSA 10.1-20 and 20.1-50 ng/mL, respectively. The AUCs of phi (0.79 and 0.89, for these two groups, respectively) were also significantly higher than tPSA (0.57 and 0.63, respectively), both P 0.0001. If a phi ≤35 was used as the cutoff, 599/1538 (39%) biopsies could have been avoided at a cost of missing small numbers of PCa patients: 49 (7.93%) PCa patients, including 18 (3.69%) high-grade tumors.Results from this study suggest that phi can be used to predict PCa and high-grade disease in Chinese men with high PSA levels (10 ng/mL).

BACKGROUND We reported that some, but not all single nucleotide polymorphisms (SNPs) in select immune response genes are associated with prostate cancer, but not individually with the prevalence of intraprostatic inflammation in the Prostate Cancer Prevention Trial (PCPT) placebo arm. Here, we investigated whether these same SNPs are associated with risk of lower- and higher-grade prostate cancer in men randomized to finasteride, and with prevalence of intraprostatic inflammation among controls. Methods A total of 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 were genotyped in 625 white prostate cancer cases, and 532 white controls negative for cancer on an end-of-study biopsy nested in the PCPT finasteride arm. We used logistic regression to estimate log-additive odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history. RESULTS Minor alleles of rs2243250 (T) in IL4 (OR = 1.46, 95% CI 1.03-2.08, P-trend = 0.03), rs1800896 (G) in IL10 (OR = 0.77, 95% CI 0.61-0.96, P-trend = 0.02), rs2430561 (A) in IFNG (OR = 1.33, 95% CI 1.02-1.74; P-trend = 0.04), rs3747531 (C) in MSR1 (OR = 0.55, 95% CI 0.32-0.95; P-trend = 0.03), and possibly rs4073 (A) in IL8 (OR = 0.81, 95% CI 0.64-1.01, P-trend = 0.06) were associated with higher- (Gleason 7-10; N = 222), but not lower- (Gleason 2-6; N = 380) grade prostate cancer. In men with low PSA (

Background Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa). Objective To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease. Design, setting, and participants A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics. Outcome measurements and statistical analysis Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher’s exact test. Results and limitations Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10–6). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10–5), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10–6), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10–9); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10–13); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02). Conclusions In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment. Patient summary Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease.

BACKGROUND Family history (FH) of prostate cancer (PCa) in Chinese population is poorly understood. The objective of this study is to evaluate the association between FH and PCa in a Chinese biopsy cohort. METHODS Consecutive patients who received 10 to 12 core systematic prostate biopsies from April 2013 to October 2018 in three medical centers were enrolled in this study. Demographic information and clinical information were obtained through prebiopsy questionnaire, including cancer FH, age, and total prostate-specific antigen (tPSA). RESULTS Of 2321 patients, 83 (3.6%) were reported a FH of PCa. The positive biopsy rate in these patients was 54.2%, significantly higher than the patients without the family history of PCa (42.6%; relative risk [RR] = 1.27; P = .024). In patients with positive FH of breast cancer gene (BRCA)-related cancers (breast, ovarian, and prostate cancer, n = 154), 74 (48.1%) were diagnosed as PCa, higher than those without FH (42.7%; RR = 1.13; P = .112). Multivariate logistic regression analysis (after adjusting for age and tPSA values) showed that there was 2.1-fold increased risk of PCa in patients with positive FH of PCa (P = .005), and 1.6-fold increased risk in patients with positive FH of BRCA-related cancers (P = .019). However, there was no significant association between FH of PCa or BRCA-related cancer and high-grade PCa after adjusting age and tPSA level (P = .404 for PCa, P = 0.991 for BRCA-related cancers). CONCLUSIONS Patients with positive FH of PCa had 2.1-fold higher risk of PCa, and patients with positive FH of BRCA-related cancers had 1.6-fold higher risk in this biopsy cohort of Chinese population. Patients with positive FH of PCa or BRCA-related cancers would have earlier age at onset of PCa.

INTRODUCTION AND OBJECTIVES:Germline mutations in the BRCA1, BRCA2 and ATM genes have been reported to be associated with clinically aggressive and/or lethal prostate cancer (PCa). However, whether...