Prostate Cancer Risk Variants Research Articles

Variants in Vitamin D-related Genes and Prostate Cancer Risk in Black Men.

The relationship between vitamin D and prostate cancer has primarily been characterized among White men. However, Black men have higher prostate cancer incidence and mortality rates, chronically low circulating vitamin D levels, and ancestry-specific genetic variants in vitamin D-related genes. Here, we examine six critical genes in the vitamin D pathway and prostate cancer risk in Black men. We assessed a total of 69 candidate variants in six genes ( GC, CYP27A1, CYP27B1, CYP24A1, VDR , and RXRA ) including functional variants previously associated with prostate cancer and circulating 25(OHD) in White men. Associations with prostate cancer risk were examined using genome-wide association study data for approximately 10,000 prostate cancer cases and 10,000 controls among Black men and over 85,000 cases and 91,000 controls among White men. A statistical significance threshold of 0.000724 was used to account for the 69 variants tested. None of the variants examined were significantly associated with prostate cancer risk among Black men after multiple comparison adjustment. Four variants tested P<0.05 in Black men, including two in RXRA (rs41400444 OR=1.09, 95% CI: 1.01-1.17, P = 0.024 and rs10881574 OR = 0.93, 0.87-1.00, P = 0.046) and two in VDR (rs2853563 OR = 1.07, 1.01-1.13, P = 0.017 and rs1156882 OR = 1.06, 1.00-1.12, P = 0.045). Two variants in VDR were also positively associated with risk in White men (rs11568820 OR = 1.04, 1.02-1.06, P = 0.00024 and rs4516035 OR = 1.03, 1.01-1.04, P = 0.00055). We observed suggestive non-significant associations between genetic variants in RXRA and VDR and prostate cancer risk in Black men. Future research exploring the relationship of vitamin D with cancer risk in Black men will need larger sample sizes to identify ancestry-specific variants relevant to risk in this population.

Effect of polygenic risk score for clinically significant prostate cancer in a screening program: The BARCODE 1 study results.

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

Abstract 6146: Characterizing underlying molecular mechanisms of prostate cancer risk variants identified from multi-ethnic GWAS

Abstract Prostate cancer (PCa) is a complex disease with the second leading cause of cancer death in US males. Multi-ethnic genome-wide association studies (GWAS) identified a thousand genetic variants associated with PCa risk in different races. However, the majority of risk variants are located in non-coding regions, making it challenging to understand their contribution to PCa risk. Non-coding regions include functional regulatory elements (REs) such as promoters and enhancers, whose activity can be evaluated by histone modification H3K4me3 and H3K27ac, respectively. In this study, we integrated PCa risk variants with hundreds of H3K4me3 and H3K27ac ChIP-seq data from normal and cancer prostate cell lines and tissues, finding 122 variants in promoters and 301 variants in enhancers. Enhancers are distal to promoters, and they form loops to regulate gene expression, mediated by transcription factors (TFs). Enhancer activities are tightly associated with cell fate. Genetic variants can affect the activity of enhancers by changing the binding preference of TFs and such changes can affect chromatin interactions and dysregulate gene expression. We hypothesize that allele changes of enhancer variants contribute to PCa risk differently among individuals from different ancestries, leading to the development of heterogeneous PCa molecular subgroups, characterized by genetic alterations including TMPRSS2-ERG fusion. By integrating H3K27ac ChIP-seq data from prostate cell lines derived from European (EUR) and African (AFR) ancestries, we found 185 risk variants in enhancers in EUR cell lines and 69 risk variants in enhancers in AFR cell lines. Next, we integrated patient tissue-derived H3K27ac ChIP-seq data and performed chromatin quantitative trait loci (cQTL) and allelic imbalance (AI) analyses to determine risk variants associated with enhancer activity. Among the 185 risk enhancer variants in EUR and 69 in AFR cell lines, we found 130 and 46 with significant association, respectively. To determine TFs that change binding upon allele change of enhancer risk variants, we integrated hundreds of TF ChIP-seq data from prostate cell lines and tissues. Among the 185 risk enhancer variants in EUR and 69 in AFR cell lines, we found 142 and 44 variants bound by TFs, respectively. When we further performed cQTL and AI analyses for FOXA1, HOXB13, and AR, we found 87 and 29 variants significantly associated with TF binding affinity, respectively. Moreover, we found that these associations differ between TMPRSS2-ERG fusion positive and negative tumors. To identify the target genes of enhancer risk variants, we are currently integrating chromatin interaction data including Hi-C and Micro-C. Overall, this study provides valuable insights into the underlying molecular mechanisms of risk variants in various populations and individuals which lead to the development of heterogeneous PCa subgroups. Citation Format: Zexun Wu, Andrew Vu, Ethan S. Nelson-Moore, Huan Cao, Suhn K. Rhie. Characterizing underlying molecular mechanisms of prostate cancer risk variants identified from multi-ethnic GWAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6146.

Abstract 6616: Polygenic risk score associated with risk of upgrading and tumor features in a prospective cohort of prostate cancer patients on active surveillance

Abstract BACKGROUND: Active surveillance (AS) is now the preferred treatment strategy for the &amp;gt;50% of prostate cancer (PCa) patients diagnosed with low-risk disease, where five-year survival rates are &amp;gt;99%. However, AS requires frequent and costly healthcare visits. In a case-only study of AS patients, we investigated whether polygenic risk scores (PRS) could identify patients who may benefit from intensive vs passive surveillance to reduce these burdens. METHODS: This study included 1,220 PCa patients on AS in the Canary Prostate Active Surveillance Study (PASS). A previously developed multi-ancestry PRS of 451 PCa risk variants (PRS451) was constructed in PASS, along with a PRS of 400 variants, excluding 51 PSA-associated variants (PRS400). Outcomes included upgrading and extreme upgrading at follow up and prostate volume, PSA, percent of biopsy cores with cancer, and Gleason grade at diagnosis. We investigated PRS associations with risk of upgrading with Cox proportional hazards regression adjusting for age at diagnosis and 10 principal components (PCs) of ancestry. Associations with risk of extreme upgrading were performed similarly but with a competing risk analysis, where the competing event was treatment. Discriminative ability was evaluated with Harrell’s C-index. To better account for population structure, we also fit mixed models with fixed effects for PRS, age at diagnosis, and 10 PCs, with a random effect for a genetic relationship matrix. RESULTS: Of the 1,220 AS patients, 38.5% (n=470) upgraded during the median 4.2 years of follow up and 85% (n=1041) self-reported as non-Hispanic White. In time-to-event analyses, each SD unit increase in PRS451 was associated with a 23% increased risk of upgrading (P=4.2 × 10−5), while PRS400 was associated with a 27% increased risk (P=1.6 × 10−6). PRS were similarly associated with 21% (95% CI=1.02-1.44, P=0.03) and 27% (95% CI=1.06-1.52, P=0.01) increased risk of extreme upgrading, respectively. Compared to a model with age at diagnosis, PCs, and clinical risk factors (C-index=0.617, 95% CI=0.590-0.644), including PRS400 slightly improved the ability to detect risk of upgrading (C-index=0.632, 95% CI=0.604-0.659). Mixed model results were highly consistent. Each SD unit increase in PRS400 was associated with 1.38 higher percentage points of biopsy cores with cancer (95% CI=0.76-2.00, P=1.1 × 10−5), 1.48 cc smaller prostate volume (95% CI=-2.82, -0.14, P=0.03), and 0.18 ng/mL higher PSA (95% CI=0.01-0.35, P=0.05) at diagnosis. Except for PSA, associations were similar or weaker for PRS451. CONCLUSION: In patients on AS, high PRS was associated with increased risk of upgrading, extreme upgrading, smaller prostate volume, and possibly tumor multifocality. As such, PRS could inform the intensity of surveillance for low-risk PCa patients, reducing the burden of AS for patients with low risk of disease progression. Citation Format: Louisa B. Goss, Menghan Liu, Yingye Zheng, Boya Guo, David V. Conti, Christopher A. Haiman, William J. Catalona, John S. Witte, Daniel W. Lin, Lisa F. Newcomb, Burcu F. Darst. Polygenic risk score associated with risk of upgrading and tumor features in a prospective cohort of prostate cancer patients on active surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6616.

Abstract B111: Population genetics identifies distinct subsets of prostate cancer risk variants between men of European, African and East Asian ancestry

Abstract Introduction Genome-wide association studies (GWAS) have identified Single Nucleotide Polymorphisms (SNPs) or variants associated with prostate cancer risk. The contribution of human genetic variation to racial disparities in prostate cancer is still not clearly understood. Men of African ancestry have the highest risk of prostate cancer, followed by European ancestry and lowest in men with East Asian ancestry. Prostate cancer is the most common cancer in human males, but non-human large primates do not develop prostate cancer naturally. This study investigated the population genetics of prostate cancer SNPs to identify those that were unique to ancestral groups, and also comparative genomics of human risk alleles and orthologous alleles in primates. Methods Prostate cancer SNPs were obtained from previous GWAS studies in the GWAS Catalog (https://www.ebi.ac.uk/gwas/home), and the GWAS Diversity Monitor Database (https://gwasdiversitymonitor.com). SNPs identified from discovery stages in AFR and EAS populations were included even when they did not replicate in EUR populations. Using Ensemble Release 109 (https://www.ensembl.org), the risk allele frequencies (RAF) in European (EUR), African (AFR) and East Asian (EAS) populations were obtained from the 1000 Genomes project and other population genetics data available on Ensembl. Population RAFs were used to identify variants that were present in only one ancestral group and not shared by other ancestral groups. A SNP was considered unique to a population if it was present in &amp;gt;1% of that population, but present in &amp;lt;.01% of the others. The risk alleles in Homo sapiens were compared to the orthologous ancestral primate allele using genome alignments from 10 primate species. Results 520 prostate cancer-associated SNPs were identified. 484 were shared between EUR, AFR and EAS populations. 10 SNPs were unique to EUR (on chromosomes 1, 2, 5, 8, 11, 17, 21, 22), 19 to AFR (on chromosomes 1, 5, 6, 8, 13, 17, 22) and 7 to EAS (on chromosomes 2, 10, 12, 13) populations. The gene sets involved by these SNPs were different in each ancestral group, with some overlap between EUR and AFR genes sets, but no overlap with the EAS genes set. The risk allele for all the 36 SNPs that were unique to EUR, AFR or EAS populations was different from the ancestral primate allele. Conclusion Prostate cancer SNPs unique to EUR, AFR and EAS populations were identified and are likely to be driving the genetic component of prostate cancer racial disparities. The genes involved were different between populations, which could have biological consequences and lead to distinct cancer phenotypes in men from different ancestral groups. The unique SNPs all had alleles different from the ancestral primate allele, suggesting that these variants emerged after human speciation and ‘Out of Africa’ human migration events. Citation Format: Chidi N. Molokwu, Evi O. Useh, Suresh Venugopal. Population genetics identifies distinct subsets of prostate cancer risk variants between men of European, African and East Asian ancestry [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B111.

Joint associations between established genetic susceptibility loci, pesticide exposures, and risk of prostate cancer

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06–1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09–2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

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

Clinical Rounds.

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Systematic fine-mapping and functional studies of prostate cancer risk variants

To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes. Our fine-mapping analysis yielded 3,395 likely causal variants, and multiscale functional annotation linked them to 487 target genes. We prioritized rs10486567 as a genome-wide top-ranked SNP and predicted HOTTIP as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. HOTTIP overexpression in enhancer-KO cell lines rescued defective invasive migration. Furthermore, we found that rs10486567 regulates HOTTIP through allele-specific long-range chromatin interaction.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

BackgroundGenetic factors play an important role in prostate cancer (PCa) susceptibility. ObjectiveTo discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participantsWe conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. Outcome measurements and statistical analysisCommon 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 limitationsNine 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). ConclusionsThis 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 summaryIn 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.

Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years.

Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown. We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer-specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span. During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer-specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57-8.66] for prostate cancer and 4.84 (95% CI, 2.59-9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%-100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years. Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.

Abstract 6242: Association of prostate cancer risk variants with gene expression in prostate stroma

Abstract Background: Prostate cancer genome-wide association studies have identified &amp;gt;260 germline risk variants which provide strong risk prediction for prostate cancer. Functional interpretation and biological mechanisms of these risk variants are not always clear. Many of the prostate cancer risk variants are expression quantitative trait loci (eQTLs), but studies have mostly been performed in tumor or epithelial-enriched normal prostate tissue. Given emerging evidence supporting that stroma contributes to the carcinogenic process, we examined the associations of prostate cancer risk variants with the expression of genes in prostate stroma. Methods: We generated mRNA expression data for 13,577 genes with the Illumina TruSeq RNA Exome library preparation kit from stromal samples in specimens from participants of the Health Professionals Follow-up Study and Physicians’ Health Study cohorts. Specifically, we profiled 172 stromal samples adjacent to tumor and 86 paired stroma distant from tumor. We included 264 prostate cancer risk variants genotyped data and imputed using a common reference panel (1,000 Genomes Phase I release). We performed cis- (≤1 Mb from the SNP (single nucleotide polymorphism) to the gene) and trans- eQTL analyses using a linear regression model in the R package Matrix eQTL. Results: Thirty-four SNPs were significantly (P &amp;lt; 0.01) associated with cis-expression of 41 nearby genes in prostate stroma adjacent to tumor, and 41 SNPs with 52 nearby genes for stroma distant from tumor. Genome-wide, 86 SNPs were significantly (FDR &amp;lt; 0.10) associated with the expression of 126 genes in stroma adjacent to tumor, and 64 SNPs with 291 genes for stroma distant from tumor. Conclusions: This is the first study to comprehensively examine associations between prostate cancer risk variants and gene expression in prostate stroma. We observed some previous reported associations but also novel associations which may suggest genes that contribute to prostate cancer risk within the stromal tissue. Identifications of eQTLs within prostate stroma may suggest potential mechanisms in specific cell types for their effect on disease. Citation Format: Chaoran Ma, Yinglu Zhou, Anna Plym, Giuseppe Nicolò Fanelli, Massimo Loda, Lorelei Mucci, Svitlana Tyekucheva, Kathryn Penney. Association of prostate cancer risk variants with gene expression in prostate stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6242.

Abstract 1441: Genetic determinants of PSA levels improve prostate cancer screening

Abstract Prostate-specific antigen (PSA) screening for prostate cancer (PCa) remains controversial due to poor sensitivity and specificity that lead to overdiagnosis and overtreatment. The aim of our study is to characterize genetic determinants of PSA levels in cancer-free men in order to personalize PCa screening. We hypothesize that test accuracy may be improved by accounting for PSA variation that is due to genetic factors and does not reflect PCa. We conducted the largest ever genome-wide association study (GWAS) of PSA in men without PCa (N=95,768; 85,924 predominantly European ancestry) using data from the UK Biobank, BioVU, PLCO, and Kaiser Permanente cohorts. Our GWAS discovered 129 PSA-associated variants (P&amp;lt;5×10-8), 82 of which were novel. A polygenic score (PGSPSA) comprised of these 129 variants was successfully validated in two cancer prevention trials: PCPT (n=5737) and SELECT (n=22,247). PGSPSA explained 7.3% (p=7.0×10-98) of variation in baseline PSA in PCPT and 8.7% (p=7.0×10-476) in SELECT. Importantly, PGSPSA was not associated with PCa status in PCPT (OR=0.98, p=0.71) or SELECT (OR=1.04, p=0.98), which confirms that it reflects benign PSA variation. Potential clinical utility of PSA genetic adjustment was explored by examining reclassification at thresholds used for biopsy referrals in a real-world setting at Kaiser Permanente. We estimated that correction using PGSPSA would have avoided 21.2% of negative biopsies in non-cases. Reclassification below the biopsy referral threshold was also more common in cases, particularly with low-grade disease with Gleason score &amp;lt;7 (7.3% below vs. 2.6% above). Overall, genetic correction of PSA appeared to improve the accuracy of referral decisions, with a Net Reclassification Index of 0.148. Next, we evaluated genetically adjusted PSA in the context of detection of aggressive PCa, defined as Gleason score ≥7, PSA ≥10 ng/mL, T3-T4 stage, and/or distant or nodal metastases. Genetically adjusted baseline PSA was more robustly associated with aggressive PCa than observed PSA and yielded a higher area under the curve (AUC) in PCPT (OR=3.03, p=3.5×10-7; AUC: 0.72 vs. 0.68) and SELECT (OR=3.37, p=3.5×10-11; AUC: 0.78 vs. 0.74) when added to a baseline model with age and trial arm. Furthermore, genetically adjusted PSA provides complementary information to PCa risk variants. In PCPT, a logistic regression model that included genetically corrected PSA and the 269-variant PGSPCa achieved a significantly higher AUC than PGSPCa-269 alone for aggressive PCa (AUC: 0.73 vs. 0.65, p=3.3×10-4) and overall PCa (AUC=0.69 vs. 0.66, p=3.3×10-6). Our work provides evidence that accounting for genetic determinants of PSA has the potential to reduce unnecessary testing and overdiagnosis of low-risk PCa, as well as increase detection of aggressive disease. Larger and more diverse study populations are required to fully characterize the genetic basis of PSA variation and optimize its clinical utility. Citation Format: Linda Kachuri, Rebecca E. Graff, Sonja I. Berndt, Mitchell Machiela, Neal D. Freedman, Stephen J. Chanock, John P. Shelley, Kerry Schaffer, Jonathan D. Mosley, Phyllis J. Goodman, Cathee Till, Ian Thompson, Robert J. Klein, Stephen K. Van Den Eeden, Thomas J. Hoffmann, John S. Witte. Genetic determinants of PSA levels improve prostate cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1441.

Prostate Cancer Susceptibility Loci Identified in GATA2 and ZMIZ1 in Chinese Population.

Background Common genetic risk variants for prostate cancer (PCa) have been identified at approximately 170 loci using genome-wide association studies (GWAS), most of which were identified in European populations. Recently, GWAS were applied to a large Japanese cohort and identified 12 novel susceptibility loci associated with PCa risk. In this study, we aim to investigate PCa susceptibility loci in the Chinese population. The study data will be used to promote PCa risk control in China. Methods A total of 235 PCa patients and 252 control subjects (all unrelated) were enrolled in this case-control PCa study. Nine single nucleotide polymorphisms (SNPs) were genotyped in GATA2 (rs73862213, rs2335052, and rs10934857), ZMIZ1 (rs704017, rs77911174, and rs3740259), and SUN2 (rs78397383, rs5750680, and rs138705) genes. The associations between the candidate SNPs and PCa were analyzed using multiple-factor logistic regression and haplotype analysis. Results The allele frequency distributions of rs73862213 and rs2335052 in the GATA2 gene and rs704017 and rs77911174 in the ZMIZ1 gene were found to be significantly different between PCa cases and controls. Haplotype analysis revealed that the G-C-A haplotype of the GATA2 gene (order of SNPs: rs73862213-rs2335052-rs10934857) and the G-G-G haplotype of the ZMIZ1 gene (order of SNPs: rs704017-rs77911174-rs3740259) were associated with increased PCa risk. None of the SUN2 haplotypes were associated with PCa. Conclusions Our study data indicates that the minor alleles of rs73862213 and rs2335052 in the GATA2 gene and rs704017 and rs77911174 in the ZMIZ1 gene were associated with increased PCa risk. These findings greatly extended our knowledge of the etiology of PCa.

Abstract PO-163: Genome-wide polygenic risk score of prostate cancer in African and European ancestry men

Abstract Genome-wide polygenic risk scores (PRS) are reported to have higher performance than standard genome-wide significant PRS across numerous complex traits. We evaluated the ability of genome-wide PRS to evaluate prostate cancer risk compared to our recently developed and highly predictive multi-ancestry PRS of 269 fine-mapped and established prostate cancer risk variants. Genome-wide PRS approaches included LDpred2, PRS-CSx, and EB-PRS. Models were trained using the largest and most diverse prostate cancer GWAS to date of 107,247 cases and 127,006 controls, which was previously used to develop the multi-ancestry PRS of 269 variants. For each approach, we constructed the PRS using population-specific weights (i.e., African or European) and multi-ancestry weights, which were calculated across men from African, European, East Asian, and Hispanic populations in our previous GWAS. Resulting models were tested in independent samples of 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,045 cases and 191,835 controls of European ancestry from the UK Biobank. Across all approaches, multi-ancestry weighted PRS had either similar or stronger performance compared to population-specific weighted PRS, both in terms of area under the curve (AUC) and odds of prostate cancer. Among the genome-wide PRS approaches, PRS-CSx constructed with multi-ancestry weights had the best performance, with AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men. Based on PRS-CSx, African and European ancestry men in the top 90-100% PRS decile relative to men in the median 40-60% PRS category had odds of prostate cancer of 2.67 (95% CI=2.00-3.55) and 4.17 (95% CI=3.87-4.50), respectively. However, the PRS constructed using 269 fine-mapped variants had larger AUCs in both African (0.679, 95% CI=0.659-0.700) and European ancestry men (0.845, 95% CI=0.841-0.849), with African and European ancestry men in the top PRS decile having larger odds of prostate cancer (3.53, 95% CI=2.66-4.69 and 4.20, 95% CI=3.89-4.53, respectively). We are currently further validating these findings in diverse men from Million Veteran's Program. This investigation suggests that genome-wide PRS may not improve the ability to distinguish prostate cancer compared to our genome-wide significant PRS and that a multi-ancestry approach to constructing PRS leads to similar or better performance than a population-specific approach. Citation Format: Burcu F. Darst, Ravi K Madduri, Alexis A. Rodriguez, Xin Sheng, Rosalind A. Eeles, Zsofia Kote-Jarai, John M. Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman. Genome-wide polygenic risk score of prostate cancer in African and European ancestry men [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-163.

Abstract PO-197: Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry

Abstract Introduction: Prostate Cancer (PCa) risk is influenced by both rare germline pathogenic variants (GPVs) in DNA damage repair genes and common variants as measured by polygenic risk scores (PRS) however, the combined effect of GPVs and PRS on PCa risk in men of African ancestry has not been investigated. Methods: We examined the combined effect of rare GPVs and PRS on PCa risk in 1,795 PCa cases and 1,424 controls of African ancestry men from the Multiethnic Cohort, the Los Angeles Study of Aggressive Prostate Cancer, and the Uganda Prostate Cancer Study. GPVs in 19 DNA genes were defined as clinically validated missense variants and variants that alter the protein sequence. The PRS was constructed as a weighted sum of 267 established PCa risk variants. The combined effect of the PRS and GPV status on PCa risk was evaluated using logistic regression models adjusting for age, study, and the first 10 principal components of ancestry to account for population stratification. Results: We identified 91 GPVs carried by 31 controls and 68 cases. Among GPV non-carriers, compared to those with average PRS (33.3-66.7%), odds ratios for PCa ranged from 0.56 (95% CI=0.45-0.70; P=1.2E-7) in low PRS men (0-33.3%) to 3.04 (95% CI=2.54-3.63; P=5.6E-35) in high PRS men (66.7-100%). Among GPV carriers, odds ratios for PCa ranged from 2.09 (95% CI=0.85-5.12; P=0.11) in low PRS men to 5.03 (95% CI=2.37-10.66; P=2.5E-5) in high PRS men, compared to GPV non-carriers with average PRS. Next, we restricted GPVs to ATM, BRCA2, PALB2, and NBN[BD2] (n=51 variants carried by 8 controls and 44 cases), which we previously reported as being the genes most strongly associated with advanced PCa in this population and study sample. Among GPV non-carriers, odds ratios for PCa ranged from 0.56 (95% CI=0.46-0.71; P=2.7E-7) in low PRS men to 5.03 (95% CI=0.85-5.12; P=0.11) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.08 (95% CI=0.58-7.49; P=0.26) in low PRS men to 18.06 (95% CI=4.24-76.84; P=9.0E-5) in high PRS men, compared to average PRS GPV non-carriers. When comparing aggressive cases to controls, considering the top four genes, GPV non-carrier odds ratios for PCa ranged from 0.52 (95% CI=0.40-0.70; P=6.2E-6) in low PRS men to 3.16 (95% CI=2.56-3.91; P=1.6E-26) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.97 (95% CI=073-12.16; P=0.13) in low PRS men to 23.58 (95% CI=5.39-103.20; P=2.7E-5) in high PRS men, compared to average PRS GPV non-carriers. Conclusion: We found that PCa risk in African ancestry men carrying GPVs in DNA damage repair and cancer predisposition genes, particularly ATM, BRCA2, PALB2, and NBN, varied depending on an individual's PRS. This implies that to comprehensively assess genetic risk of PCa, it is important to consider both rare and common variants. These findings could have implications for risk stratification in this high-risk population and emphasize the need for larger genetic studies of PCa in African ancestry men to identify and characterize genetic risk factors in this population. Citation Format: Raymond W. Hughley, Burcu F. Darst, Marco Matejcic, Yesha Patel, Jenna Lilyquist, Steven N. Hart, Eric C. Polley, Lucy Xia, Xin Sheng, Alexander Lubmawa, Sue A. Ingles, Lynne Wilkens, Loïc L. Marchand, Stephen Watya, Fergus J. Couch, David V. Conti, Christopher A. Haiman. Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-197.

Abstract LB011: Meta-analysis in more than 80,000 men of African ancestry identified nine novel variants associated with prostate cancer

Abstract In search for common genetic variants contributing to the risk of prostate cancer in men of African ancestry, we conducted a meta-analysis of GWAS summary statistics from the African Ancestry Prostate Cancer Consortium (AAPC; 12,643 cases and 16,627 controls) and the VA Million Veteran Program (6,107 cases and 47,412 controls). A total of 29,896,808 common (minor allele frequency (MAF) &amp;gt; 0.01) genotyped and imputed variants (r2 &amp;gt; 0.3) were meta-analyzed in a total of 18,750 prostate cancer cases and 64,039 controls. Of the 269 established risk variants for prostate cancer, 265 were polymorphic and 168 were nominally (P&amp;lt;0.05) associated with prostate cancer risk with directionally consistent effect estimates, of which 44 reached the genome-wide significance (P&amp;lt;5x10-8). Of the 3,018 genome-wide significant variants, eight were considered novel susceptibility loci for prostate cancer in men of African ancestry. Of the eight variants, five were only found in populations of African ancestry (MAF 2% - 34%) but not in European or Asian populations, and two were substantially more common in African ancestry populations (MAF 40%) than in other populations (MAF &amp;lt; 8%). One of the novel variants, rs60985508 (odds ratio (OR) = 1.12 [1.08 - 1.15]; P = 2.93×10-13; MAF = 34%), introduces a stop codon in exon 24 in the prostate-specific gene anoctamin 7 (ANO7), a known prostate cancer susceptibility gene. A polygenic risk score including 273 variants (265 of 269 established risk variants and 8 novel variants from this analysis) conferred an increased prostate cancer risk for men in the 90 - 100th percentile (OR = 3.91 [3.50 - 4.36]) and those in the 99 - 100th percentile (OR = 7.05 [5.51 - 9.02]), compared to men in the 40-60th percentile. These estimates were higher than what was observed with the PRS of 265 variants (90 - 100th percentile: OR = 3.49 [3.13 - 3.90]; 99 - 100th percentile: OR = 6.40 [4.99 - 8.21]). Our finding of 8 novel susceptibility loci for prostate cancer may improve risk prediction for men of African Ancestry and provide further insight into the underlying biology of prostate cancer. Citation Format: Fei Chen, Ravi K. Madduri, Xin Sheng, Alex Rodriguez, Alisha Chou, Todd L. Edwards, Stephen K. Van Den Eeden, Rosalind A. Eeles, John S. Witte, Michael B. Cook, William J. Blot, David V. Conti, John M. Gaziano, Amy C. Justice, Christopher A. Haiman, VA Million Veteran Program and PRACTICAL/ELLIPSE Consortium. Meta-analysis in more than 80,000 men of African ancestry identified nine novel variants associated with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB011.

Abstract NG03: Multiethnic prostate cancer GWAS meta-analysis identifies novel variants, improves genetic risk prediction across populations, and informs biological mechanisms of prostate cancer

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

Prostate cancer risk variants of the HOXB genetic locus

The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case–control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E−9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E−11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E−8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.

Combined Effect of a Polygenic Risk Score and Rare Genetic Variants on Prostate Cancer Risk

Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man’s lifetime risk of prostate cancer. Patient summaryWe found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual’s genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.