Pan-cancer proteogenomics characterization of tumor immunity.

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

The role community-based healthcare providers play in managing hard-to-heal wounds.

It is common for community-based healthcare providers (CHPs)-many of whom have not received specialised training in wound care-to deliver initial and ongoing management for various wound types and diverse populations. Wounds in any setting can rapidly transition to a stalled, hard-to-heal wound (HTHW) that is not following a normal healing trajectory. Failure to recognise or address issues that cause delayed healing can lead to increased costs, healthcare utilisation and suffering. To encourage early intervention by CHPs, a panel of wound care experts developed actionable evidence-based recommendations for CHPs delineating characteristics and appropriate care in identifying and treating HTHWs. A HTHW is a wound that fails to progress towards healing with standard therapy in an orderly and timely manner and should be referred to a qualified wound care provider (QWCP) for advanced assessment and diagnosis if not healed or reduced in size by 40%-50% within 4 weeks. HTHWs occur in patients with multiple comorbidities, and display increases in exudate, infection, devitalised tissue, maceration or pain, or no change in wound size. CHPs can play an important initial role by seeing the individual's HTHW risk, addressing local infection and providing an optimal wound environment. An easy-to-follow one-page table was developed for the CHP to systematically identify, evaluate and treat HTHWs, incorporating a basic toolkit with items easily obtainable in common office/clinic practice settings. A flow chart using visual HTHW clinical cues is also presented to address CHPs with different learning styles. These tools encourage delivery of appropriate early interventions that can improve overall healthcare efficiency and cost.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

A brief nonattachment intervention based on the three marks of existence: development, rationale, and initial evidence.

BACKGROUND: The practices described in Buddhist philosophy are essentially a suite of non-theistic cognitive and behavioral interventions designed to induce nonattachment (N-A), which can be defined in terms of the absence of a need for one's personal reality to be other than it is. Although meditative practices have received attention in multiple literatures, the cognitive analogs to these behaviorally-oriented practices have not. DESIGN: Two experiments involving undergraduate participants (total N = 239; M age = 19.04) investigated whether the provision of wisdom related to the Three Marks of Existence (i.e., some degree of suffering is inevitable, there is impermanence, and many events are not in our control) could result in (1) higher nonattachment attitudes, (2) lower threat appraisals, (3) lower stressor reactivity, and (4) shorter emotion reaction durations. RESULTS: With moderate to large effect sizes, the Three Marks trainings (relative to placebo or control conditions) resulted in (1) higher nonattachment attitudes, (2) lower threat appraisals, (3) no differences in negative emotional intensity, but 4) shorter emotion durations. CONCLUSIONS: These results provide preliminary evidence that enduring cognitive trainings such as the Three Marks can be an effective tool to increase acceptance-related attitudes while attenuating negative reactivity.

Examination of fully automated mammographic density measures using LIBRA and breast cancer risk in a cohort of 21,000 non-Hispanic white women.

BACKGROUND: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding. METHODS: We conducted a cohort study among 21,150 non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were 40-74 years at enrollment, followed for up to 10 years, and had archived processed screening mammograms acquired on Hologic or General Electric full-field digital mammography (FFDM) machines and prior Cumulus density assessments available for analysis. Dense area (DA), non-dense area (NDA), and percent density (PD) were assessed using LIBRA software. Cox regression was used to estimate hazard ratios (HRs) for breast cancer associated with DA, NDA and PD modeled continuously in standard deviation (SD) increments, adjusting for age, mammogram year, body mass index, parity, first-degree family history of breast cancer, and menopausal hormone use. We also examined differences by machine type and breast view. RESULTS: The adjusted HRs for breast cancer associated with each SD increment of DA, NDA and PD were 1.36 (95% confidence interval, 1.18-1.57), 0.85 (0.77-0.93) and 1.44 (1.26-1.66) for LIBRA and 1.44 (1.33-1.55), 0.81 (0.74-0.89) and 1.54 (1.34-1.77) for Cumulus, respectively. LIBRA results were generally similar by machine type and breast view, although associations were strongest for Hologic machines and mediolateral oblique views. Results were also similar during the first 2 years, 2-5 years and 5-10 years after the baseline mammogram. CONCLUSION: Associations with breast cancer risk were generally similar for LIBRA and Cumulus density measures and were sustained for up to 10 years. These findings support the suitability of fully automated LIBRA assessments on processed FFDM images for large-scale research on breast density and cancer risk.

Proteogenomic data and resources for pan-cancer analysis.

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data.

Dysregulated Emotion and Trying Substances in Childhood: Insights from a Large Nationally Representative Cohort Study.

OBJECTIVE: Transdiagnostic perspectives on the shared origins of mental illness posit that dysregulated emotion may represent a key driving force behind multiple forms of psychopathology, including substance use disorders. The present study examined whether a link between dysregulated emotion and trying illicit substances could be observed in childhood. METHOD: In a large (N = 7,418) nationally representative sample of children (Mage = 9.9), individual differences in emotion dysregulation were indexed using child and parent reports of frequency of children's emotional outbursts, as well as children's performance on the emotional N-Back task. Two latent variables, derived from either parental/child-report or performance-based indicators, were evaluated as predictors of having ever tried alcohol, tobacco, or marijuana. RESULTS: Results showed that reports of dysregulated emotion were linked to a greater likelihood of trying both alcohol and tobacco products. These findings were also present when controlling for individual differences in executive control and socioeconomic status. CONCLUSIONS: These results suggest that well-established links between dysregulated negative emotion and substance use may emerge as early as in childhood and also suggest that children who experience excessive episodes of uncontrollable negative emotion may be at greater risk for trying substances early in life.

Genetically adjusted PSA levels for prostate cancer screening.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5): EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6, and RP11-327J17.2. Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.

Second-to-Second Affective Responses to Images Correspond With Affective Reactivity, Variability, and Instability in Daily Life.

Two distinct literatures have evolved to study within-person changes in affect over time. One literature has examined affect dynamics with millisecond-level resolution under controlled laboratory conditions, and the second literature has captured affective dynamics across much longer timescales (e.g., hours or days) within the relatively uncontrolled but more ecologically valid conditions of daily life. Despite the importance of linking these literatures, very little research has been done so far. In the laboratory, peak affect intensities and reaction durations were quantified using a paradigm that captures second-to-second changes in subjective affect elicited by provocative images. In two studies, analyses attempted to link these micro-dynamic indexes to fluctuations in daily affect ratings collected via daily protocols up to 4 weeks later. Although peak intensity and reaction duration scores from the laboratory did not consistently relate to daily scores pertaining to affect variability or instability, the total magnitude of changes in affect following images did display relationships of this type. In addition, higher peaks in the laboratory predicted larger intensity reactions to salient daily events. Together, the studies provide insights into the mechanisms through which correspondences and noncorrespondences between laboratory reactivity indices and daily affect dynamic measures can be expected.

MiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer.

Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-aware transcriptome-wide analyses can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases.

Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.

Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied whether [89Zr]11B6-PET can accurately assess EBRT-induced AR activity.Genetic and human prostate cancer mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue.EBRT increased AR pathway activity and [89Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [89Zr]11B6 uptake in prostate cancer-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels. IMPLICATIONS: hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.

Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics.

Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28-1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30-1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24-1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis.

A psychological flexibility perspective on well-being: Emotional reactivity, adaptive choices, and daily experiences.

According to psychological flexibility theory, fully experiencing one's emotions, even when they involve negative reactions, can enhance psychological well-being. In pursuit of this possibility, procedures capable of disentangling reaction intensities from reaction durations, in response to affective images, were developed and variations of this paradigm were applied in understanding variations in happiness and adaptive behavior. Consistent with psychological flexibility theory, three studies showed that more intense emotional reactions, irrespective of valence, were associated with higher levels of well-being. Two additional studies showed that happy individuals, relative to less happy individuals, exhibited more functional approach/avoidance behavior in behavior-focused tasks. Together, the results are consistent with the idea that adaptive emotion generation systems are those that flexibly adapt emotion output to concurrent emotion-related stimulation. The program of research adds to our understanding of the relationship between emotion reactivity and well-being while highlighting specific processes through which emotion and well-being interact. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Are polygenic risk scores ready for the cancer clinic?-a perspective.

To realize the goals of precision medicine in complex disease, discriminative clinical risk models are needed. One approach that has been proposed is polygenic risk scores (PRSs). PRSs incorporate information about inherited genetic risk for cancer, specifically those genetic variants that are common in the population. While PRSs are clearly associated with risk of cancer, there is an on-going debate on whether integrating PRSs into clinical practice have utility. Here, we present this important discussion to the cancer clinic. We argue that in cancer, the clinical utility of PRSs will depend on their actionability, or how such a score may guide clinical practice. In turn, the actionability depends on several factors. First, actionability depends on the discriminative power of the score, or how well it predicts who is at risk of the disease. Second, it depends on their comparative performance with respect to existing practice, as a score with good discriminative power will not be useful if there are better predictors used in the clinic. Finally, for a PRS to be useful there must also be available preventive actions. We discuss the strengths and challenges of utilizing a PRS in the context of each of these criteria, and provide insights on what is needed towards moving forward in translating PRSs into the cancer clinic. We further argue that in future studies, beyond predicting cancer risk, similarly developed PRS models may be of utility in predicting prognosis or treatment resistance.

Anxiety, depression, and substance experimentation in childhood.

Previous research has demonstrated that adults with comorbid depressive and anxiety disorders are significantly more likely to show pathological use of drugs or alcohol. Few studies, however, have examined associations of this type in children. A better understanding of the relationships between affective disorders and substance experimentation in childhood could help clarify the complex ways in which pathological substance use symptoms develop early in life. The present study included 11,785 children (Mage = 9.9) participating in the Adolescent Brain Cognitive Development (ABCD) study. Depressive and anxiety disorder diagnoses were evaluated as concurrent predictors of experimentation with alcohol and tobacco. A series of linear regressions revealed that children with either depressive or anxiety disorders were significantly more likely to experiment with alcohol or tobacco. However, children with both depressive and anxiety diagnoses were not more likely to experiment than children without a diagnosis. These results suggest that anxiety or depressive diagnoses in childhood may be associated with a greater likelihood of substance experimentation, but severe psychological distress may suppress these effects.

SNPs at SMG7 Associated with Time from Biochemical Recurrence to Prostate Cancer Death.

BACKGROUND: A previous genome-wide association study identified several loci with genetic variants associated with prostate cancer survival time in two cohorts from Sweden. Whether these variants have an effect in other populations or if their effect is homogenous across the course of disease is unknown. METHODS: These variants were genotyped in a cohort of 1,298 patients. Samples were linked with age, PSA level, Gleason score, cancer stage at surgery, and times from surgery to biochemical recurrence to death from prostate cancer. SNPs rs2702185 and rs73055188 were tested for association with prostate cancer-specific survival time using a multivariate Cox proportional hazard model. SNP rs2702185 was further tested for association with time to biochemical recurrence and time from biochemical recurrence to death with a multi-state model. RESULTS: SNP rs2702185 at SMG7 was associated with prostate cancer-specific survival time, specifically the time from biochemical recurrence to prostate cancer death (HR, 2.5; 95% confidence interval, 1.4-4.5; P = 0.0014). Nine variants were in linkage disequilibrium (LD) with rs2702185; one, rs10737246, was found to be most likely to be functional based on LD patterns and overlap with open chromatin. Patterns of open chromatin and correlation with gene expression suggest that this SNP may affect expression of SMG7 in T cells. CONCLUSIONS: The SNP rs2702185 at the SMG7 locus is associated with time from biochemical recurrence to prostate cancer death, and its LD partner rs10737246 is predicted to be functional. IMPACT: These results suggest that future association studies of prostate cancer survival should consider various intervals over the course of disease.

Association of Selective Serotonin Reuptake Inhibitor Use With Abnormal Physical Movement Patterns as Detected Using a Piezoelectric Accelerometer and Deep Learning in a Nationally Representative Sample of Noninstitutionalized Persons in the US.

Importance: Selective serotonin reuptake inhibitors (SSRIs) are a common first-line treatment for some psychiatric disorders, including depression and anxiety; although they are generally well tolerated, SSRIs have known adverse effects, including movement problems, sleep disruption, and gastrointestinal problems (eg, nausea and upset stomach). No large-scale studies using naturalistic, longitudinal, objective data have validated physical activity findings, and actigraphy data are well suited to address this task. Objectives: To evaluate whether differences in physical movement exist among individuals treated with SSRIs compared with control participants and to identify the unique features of the movement of patients treated with SSRIs. Design, Setting, and Participants: This cross-sectional study examines longitudinally collected wearable movement data within a cross-sectional sample of 7162 participants from the 2005-2006 National Health and Nutrition Examination Survey (NHANES), a nationally representative population-based sample of noninstitutionalized persons in the US having both medication information and passive movement data. Statistical analysis was performed from April 1, 2021, to February 1, 2022. Exposures: The use of SSRIs (sertraline hydrochloride, escitalopram oxalate, fluoxetine hydrochloride, paroxetine hydrochloride, and citalopram hydrobromide), as reported by participants interviewed by NNHANES personnel, was the primary exposure, measured as a binary variable (taking an SSRI vs not taking an SSRI). Main Outcomes and Measures: The primary outcome was the intensity of body movement as recorded by a piezoelectric accelerometer worn on the right hip for more than 1 week. Results: Of the 7162 participants included in the study, the mean (SD) age was 33.7 (22.6) years, 266 (3.7%) were taking an SSRI, 3706 (51.7%) were female, 1934 (27.0%) were Black, 1823 (25.5%) were Mexican American, 210 (2.9%) were other Hispanic, 336 (4.7%) were other or multiracial, and 2859 (39.9%) were White (per the NHANES data collection protocol). A cross-validated, deep learning classifier was constructed that achieved fair performance predicting SSRI use (area under the curve, 0.67 [95% CI, 0.64-0.71] for the validation set and 0.66 [95% CI, 0.64-0.68] for the test set). To account for possible confounding by indication, we constructed a parallel model incorporating depression severity, finding only marginal performance improvement. When averaged across individuals and across 7 days, the results show less overall movement in the SSRI group (mean, 120.1 vertical acceleration counts/min [95% CI, 115.7-124.6 vertical acceleration counts/min]) compared with the non-SSRI control group (mean, 168.8 vertical acceleration counts/min [95% CI, 162.8-174.9 vertical acceleration counts/min]). Conclusions and Relevance: This cross-sectional study found a moderate association between passive movement and SSRI use, as well as SSRI detection capacity of passive movement using time series deep learning models. The results support the use of passive sensors for exploration and characterization of psychotropic medication adverse effects.

Prostate cancer polygenic risk score and prediction of lethal prostate cancer.

Polygenic risk scores (PRS) for prostate cancer incidence have been proposed to optimize prostate cancer screening. Prediction of lethal prostate cancer is key to any stratified screening program to avoid excessive overdiagnosis. Herein, PRS for incident prostate cancer was evaluated in two population-based cohorts of unscreened middle-aged men linked to cancer and death registries: the Västerbotten Intervention Project (VIP) and the Malmö Diet and Cancer study (MDC). SNP genotypes were measured by genome-wide SNP genotyping by array followed by imputation or genotyping of selected SNPs using mass spectrometry. The ability of PRS to predict lethal prostate cancer was compared to PSA and a commercialized pre-specified model based on four kallikrein markers. The PRS was associated with incident prostate cancer, replicating previously reported relative risks, and was also associated with prostate cancer death. However, unlike PSA, the PRS did not show stronger association with lethal disease: the hazard ratio for prostate cancer incidence vs. prostate cancer metastasis and death was 1.69 vs. 1.65 in VIP and 1.25 vs. 1.25 in MDC. PSA was a much stronger predictor of prostate cancer metastasis or death with an area-under-the-curve of 0.78 versus 0.63 for the PRS. Importantly, addition of PRS to PSA did not contribute additional risk stratification for lethal prostate cancer. We have shown that a PRS that predicts prostate cancer incidence does not have utility above and beyond that of PSA measured at baseline when applied to the clinically relevant endpoint of prostate cancer death. These findings have implications for public health policies for delivery of prostate cancer screening. Focusing polygenic risk scores on clinically significant endpoints such as prostate cancer metastasis or death would likely improve clinical utility.