Prostate Cancer Susceptibility Research Articles

Correlation between Genomic Variants and Worldwide Epidemiology of Prostate Cancer.

Prostate cancer (PCa) incidence and mortality vary across territories and populations. This can be explained by the genetic factor of this disease. This article aims to correlate the epidemiological data, worldwide incidence, and mortality of PCa with single-nucleotide polymorphisms (SNPs) associated with the susceptibility and severity of this neoplasm in different populations. Eighty-four genetic variants associated with prostate cancer susceptibility were selected from the literature through genome association studies (GWAS). Allele frequencies were obtained from the 1000 Genomes Project, and epidemiological data were obtained from Surveillance, Epidemiology, and End Results (SEER). The PCa incidence, mortality rates, and allele frequencies of variants were evaluated by Pearson’s correlation. Our study demonstrated that 12 SNPs (rs2961144, rs1048169, rs7000448, rs4430796, rs2066827, rs12500426, rs6983267, rs11649743, rs2075110, rs114798100, rs855723, and rs2075109) were correlated with epidemiological data in different ethnic groups. Ten SNPs (rs2961144, rs1048169, rs7000448, rs4430796, rs2066827, rs12500426, rs11649743, rs2075110, rs114798100, and rs2075109) were positively correlated with the mortality rate. Seven SNPs (rs1048169, rs2961144, rs7000448, rs4430796, rs2066827, rs12500426, and rs114798100) were positively correlated with incidence. Positive correlations of incidence and mortality rates were more frequent in the African population. The genetic variants investigated here are likely to predispose to PCa and could play a role in its progression and aggressiveness. This genetic study demonstrated here is promising for implementing personalized strategies to screen for prostate cancer in diverse populations.

Genetic variants and prostate cancer susceptibility

Prostate cancer (PCa) kills one man in forty five and represents the most frequently diagnosed cancer in American men. As is true with cancer, early detection through digital rectal exam and serum testing for prostate specific antigen have greatly reduced the number of fatalities yet these same methods sometimes lead to overdiagnosis and overtreatment. Previous studies have highlighted the association between single nucleotide polymorphisms (SNPs) and cancer. In our studies, we sought to find correlations between SNPs on chromosome 8 and PCa. Normal and PCa patient sequencing data was obtained from the Sequence Read Archive and then analysis pipelines were constructed to map the sequences against chromosome 8 followed by indexing and variant calling. Our studies were able to identify four SNPs specific to DNA sequences isolated from prostate cancer tissues but that were absent in normal tissues. We hope that our findings might help improve personalized medicine and possibly reduce the incidences of overdiagnosis and overtreatment of PCa.

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.

GSTT1, an increased risk factor for prostate cancer in patients with metabolic syndrome.

BackgroundGlutathione S‐transferase (GSTs) gene polymorphism and metabolic syndrome (Mets) are generally considered to be risk factors for prostate cancer (PCa). However, this conclusion is still controversial. There is a close relationship between GSTs gene polymorphism and Mets. We suspect that the effect of GSTs gene polymorphism and Mets on PCa may be the result of their joint action. As a result, the purpose of this study was to investigate the potential effect of GSTs gene polymorphism on PCa in patients with Mets.MethodsWe collected blood samples from 128 patients with PCa and 200 controls. The GSTs gene polymorphism was detected by polymerase chain reaction‐restriction fragment length polymorphism (PCR–RFLP). Age, characteristics of Mets, frequencies of GSTs gene polymorphism, total prostate volume (TPV), Gleason score, and prostate‐specific antigen (PSA) were recorded and analyzed.ResultsThere were significant differences in BMI, TG, LDL‐C, FBG, SBP, DBP, and HDL‐C among the control group, N‐PCa group, and Mets‐PCa group (p < 0.05). GSTT1 null genotype (OR = 2.844, 95% CI: 1.791–4.517), GSTM1 null genotype (OR = 2.192, 95% CI: 1.395–3.446), and GSTP1 (A/G + G/G) genotype (OR = 2.315, 95% CI: 1.465–3.657) were associated with PCa susceptibility and malignancy. Only the GSTT1 null genotype in Mets patients was positively correlated with PCa.ConclusionsOur study suggests that GSTs gene polymorphism may be a risk factor for PCa and can predict the susceptibility and malignancy of PCa. Secondly, in Mets patients, GSTT1 null genotype significantly increased the risk of PCa. GSTM1 null genotype and the effect of GSTP1 (AG + GG) on PCa were not significantly related to Mets.

Putative germline findings in tumor-only and liquid biopsy sequencing in veterans with aggressive prostate cancer.

179 Background: Tumor-only and/or liquid-biopsy based Next Generation Sequencing (NGS)-based tests, which are routinely performed in metastatic prostate cancer patients, may identify putative germline mutations. The European Society of Medical Oncology (ESMO) made recommendations on findings which should be referred for germline genetic testing; however, it is unknown the burden of genetic testing referrals that may result from implementation of these recommendations. We therefore determined the frequency of putative germline findings in Veterans with metastatic prostate cancer who have undergone NGS-based sequencing of tumor and/or cell-free DNA (cfDNA) on the Foundation Medicine (FMI) platform. Methods: This is a retrospective analysis of Veterans with FMI NGS testing results reported from January 2019-February 2021 who had prostate cancer as the submitted diagnosis and metastatic diagnosis according to a VINCI natural language processing tool. Raw variant data were extracted from FMI reports and harmonized for variant annotation. Variants were annotated using ANNOVAR. Putative germline mutations were defined as 1) likely pathogenic or pathogenic (LP/P) by Clinvar annotation and VAF&gt; 30%. Mutation rates are reported in genes recommended by ESMO to trigger referral for germline testing in all tumor types and all ages of diagnosis and proposed prostate cancer susceptibility genes ( ATM, BARD1, CHEK2). Results: 1,597 Veterans with metastatic prostate cancer underwent FMI NGS testing (63% White, 33% African American, 4% other). Median age was 66 years, with 78.6% of cases from men &gt;60 years. Of 1,597 prostate cancer patients who underwent blood or tumor testing, n=85 (5.3%) had an LP/P mutation in an ESMO-guideline gene. When mutations in ATM, BARD1 and CHEK2 were added, n=133 (8.3%) of patients had an LP/P mutation. The most commonly identified putative germline findings were in BRCA2 (n=49 patients, 3.1%). 18 patients (1.1%) had mutations in other prostate cancer risk genes on the ESMO list ( BRCA1, MLH1, MSH2, MSH6, PMS2). 18 (1.1%) of patients had putative incidental germline findings, which included mutations in PALB2, BRIP1, RAD51C, RAD51D, SDHC. No putative incidental germline mutations were identified in RET, SDHA, SDHB, SDHD, TSC2, VHL. Comparing self-identified White versus self-identified Black patients, putative germline mutation rates were nearly the same in all ESMO-referral genes combined (8.2% vs 8.5%), BRCA2 (2.9% vs 3.0%), and ATM (2.4% vs 2.1%). Conclusions: While guidelines recommend that all veterans with metastatic prostate cancer undergo germline genetic testing, significant patient and system-level barriers continue to limit access to germline genetic testing for many Veterans. Tumor-only NGS testing, with a low rate of putative incidental findings, can help to prioritize which Veterans should be referred for germline genetic testing.

Mechanistic insights into genetic susceptibility to prostate cancer.

Prostate cancer (PCa) is the second most common cancer in men and is a highly heritable disease that affects millions of individuals worldwide. Genome-wide association studies have to date discovered nearly 270 genetic loci harboring hundreds of single nucleotide polymorphisms (SNPs) that are associated with PCa susceptibility. In contrast, the functional characterization of the mechanisms underlying PCa risk association is still growing. Given that PCa risk-associated SNPs are highly enriched in noncoding cis-regulatory genomic regions, accumulating evidence suggests a widespread modulation of transcription factor chromatin binding and allelic enhancer activity by these noncoding SNPs, thereby dysregulating gene expression. Emerging studies have shown that a proportion of noncoding variants can modulate the formation of transcription factor complexes at enhancers and CTCF-mediated 3D genome architecture. Interestingly, DNA methylation-regulated CTCF binding could orchestrate a long-range chromatin interaction between PCa risk enhancer and causative genes. Additionally, one-causal-variant-two-risk genes or multiple-risk-variant-multiple-genes are prevalent in some PCa risk-associated loci. In this review, we will discuss the current understanding of the general principles of SNP-mediated gene regulation, experimental advances, and functional evidence supporting the mechanistic roles of several PCa genetic loci with potential clinical impact on disease prevention and treatment.

Inherited TP53 Variants and Risk of Prostate Cancer

BackgroundInherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. ObjectiveTo determine whether gTP53 predisposes to prostate cancer. Design, setting, and participantsThis multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort. Outcome measurements and statistical analysisWe evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer. Results and limitationsWe identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3–7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2–55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2–14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51–62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis. ConclusionsComplementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. Patient summaryInherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

H3K27ac HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility

Genome-wide association studies (GWASs) have identified more than 200 prostate cancer (PrCa) risk regions, which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues, thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirm previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g., MLPH). Interestingly, HiChIP identifies links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g., AR) that are not detected by eQTL-based methods. HiChIP predicted enhancer elements at the AR and NKX3-1 prostate cancer risk loci, and both were experimentally confirmed to regulate expression of the corresponding genes through CRISPR interference (CRISPRi) perturbation in LNCaP cells. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes.

Association of a common genetic variant (insertion/deletion) in ACE gene with prostate cancer susceptibility in a Tunisian population.

BackgroundAngiotensin‐converting enzyme (ACE) plays a pivotal role in several pathologies including cancers. The association of insertion/deletion (I/D) polymorphism of the ACE gene with prostate cancer (PC) risk remains controversial. We aimed to investigate for the first time, to our Knowledge, in North Africa the potential relationship between ACE I/D polymorphism with PC susceptibility and clinical outcomes of PC patients.MethodsThis case‐control study included 143 healthy individuals and 124 patients diagnosed with PC. Using genomic DNA, the samples were genotyped for ACE I/D polymorphism by polymerase chain reaction (PCR).ResultsWe found that The D allele is significantly associated with an increased risk of PC and D/D + D/I genotypes were at 3 times increased risk of PC ([p = 0.005], OR = 2.95, IC 95% = 1.26–7.09) compared with I/I genotype (p = 0.003, OR = 0.3, IC 95% = 0.12–0.74). We observed an association between D/D and D/I genotypes with advanced age (≥70 years) (p = 0.014; r 2 = 0.22). Furthermore, there is a significant prediction of advanced Gleason score ≥8 based on epidemiological parameters and ACE genotype (p = 0.000; R2 = 0.349), although no significant association was observed with stage and metastasis.ConclusionThe ACE I/D polymorphism is likely to predispose to PC and could play a role in PC progression and aggressiveness.

The HOXB13 variant X285K is associated with clinical significance and early age at diagnosis in African American prostate cancer patients.

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. We sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital. 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 <7 PCa, odds ratio, OR = inf; 95% Confidence Interval, 95%CI:1.05-inf, P = 0.028), as well as PCa with early age at diagnosis (2.4% carrier rate in patients <50 year vs. 0.5% carrier rate in patients ≥50 year, OR = 5.25, 95% CI:1.00-28.52, P = 0.03). While this variant is rare in the AA population (~0.2% MAF), its ancestry-specific occurrence and apparent preferential association with risk for the more aggressive disease at an early age emphasizes its translational potential as an important, novel PCa susceptibility marker in the high-risk AA population.

Large Multicohort Study Reveals a Prostate Cancer Susceptibility Allele at 5p15 Regulating TERT via Androgen Signaling-Orchestrated Chromatin Binding of E2F1 and MYC.

Aberrant telomerase reverse transcriptase (TERT) expression is crucial for tumor survival and cancer cells escaping apoptosis. Multiple TERT-locus variants at 5p15 have been discovered in association with cancer risk, yet the underlying mechanisms and clinical impacts remain unclear. Here, our association studies showed that the TERT promoter variant rs2853669 confers a risk of prostate cancer (PCa) in different ethnic groups. Further functional investigation revealed that the allele-specific binding of MYC and E2F1 at TERT promoter variant rs2853669 associates with elevated level of TERT in PCa. Mechanistically, androgen stimulations promoted the binding of MYC to allele T of rs2853669, thereby activating TERT, whereas hormone deprivations enhanced E2F1 binding at allele C of rs2853669, thus upregulating TERT expression. Notably, E2F1 could cooperate with AR signaling to regulate MYC expression. Clinical data demonstrated synergistic effects of MYC/E2F1/TERT expression or with the TT and CC genotype of rs2853669 on PCa prognosis and severity. Strikingly, single-nucleotide editing assays showed that the CC genotype of rs2853669 obviously promotes epithelial–mesenchymal transition (EMT) and the development of castration-resistant PCa (CRPC), confirmed by unbiased global transcriptome profiling. Our findings thus provided compelling evidence for understanding the roles of noncoding variations coordinated with androgen signaling and oncogenic transcription factors in mis-regulating TERT expression and driving PCa.

The impact of receptor of advanced glycation end-products polymorphisms on prostate cancer progression and clinicopathological characteristics.

The receptor for advanced glycation end products (RAGE) overexpression was suggested to be associated with prostate cancer development and poor prognosis. In this study, we focused on the correlations between the clinicopathological characteristics and susceptibility of prostate cancer and RAGE single‐nucleotide polymorphisms (SNPs). In 579 prostate cancer patients, the RAGE SNPs rs1800625, rs1800624, rs2070600 and rs184003 in patients with or without grade group upgrade were analysed with real‐time polymerase chain reaction. The results demonstrated that the prostate cancer patients who carried the RAGE SNPs rs2070600 ‘GA’ genotypic variants were significantly associated with lower risk to develop grade group upgrade. Moreover, patients with the RAGE rs1800625 ‘TC + CC’ genotypic variants were associated with higher risk of perineural invasion. In 343 prostate cancer patients who carried the RAGE rs1800625 ‘TC + CC’ genotype without grade group upgrade were correlated with higher risk of biochemical recurrence and perineural invasion. In the analysis of TCGA database, significant differences of the RAGE mRNA level were found between the normal controls and prostate cancer patients (p < 0.0001), and the pathologic stage N1 and N0 patients (p = 0.0027). The prostate cancer patients with high RAGE expression were associated with lower overall survival rate (p = 0.025). In conclusion, our results have revealed that the RAGE SNPs rs2070600 and rs1800625 were associated with the grade group upgrade of prostate cancer and clinical status. The RAGE polymorphisms may provide as a pivotal predictor to evaluate prostate cancer disease progression and prognosis.

Interleukin-10 (IL-10) gene polymorphisms and prostate cancer susceptibility: Evidence from a meta-analysis

Prostate cancer is the second most frequent cancer in men. The frequency of the prostate cancer is greatly varies in different populations of the world. Three common polymorphisms in promoter region of interleukin-10 (IL-10) gene viz. -1082A > G, -819C > T and -592C > A are extensively studied in prostate cancer with inconclusive results. So, a meta-analysis was performed to assess the association between these three IL-10 gene polymorphisms and risk of prostate cancer susceptibility. Suitable studies were retrieved by electronic databases search and odds ratios (ORs) with 95% confidence intervals (CIs) were used as association measure. All the statistical analyses were conducted in the Open Meta-Analyst program. In our meta-analysis we included 17 studies (10,718 samples), 12 studies (8810 samples) and 13 studies (7801 samples) for -1082A > G, -819C > T and -592C > A polymorphisms respectively. The result of the -592C > A polymorphism revealed low heterogeneity with no association in the overall analysis (ORAvs.C = 1.05, 95% CI = 0.99–1.12, p = 0.09, I2 = 35.89%). In ethnicity based stratified analyses, significant association was found in Caucasian population with prostate cancer using allele contrast model (ORAvs.C = 1.10, 95% CI = 1.02–1.18, p = 0.01, I2 = 19.37%), homozygote model (ORAAvs.CC = 1.32, 95% CI = 1.05–1.67, p = 0.01, I2 = 0%), and dominant model (ORAA+CAvs.CC = 1.11, 95% CI = 1.00–1.24, p = 0.04, I2 = 40.75%). No such results were found in the Asian population. In the other two polymorphisms i.e. -1082A > G and -819C > T, no significant association with prostate cancer was observed. In conclusion, results of present meta-analysis suggested that IL-10-592C > A polymorphism plays a role in the etiology of the prostate cancer in the Caucasian population.

Prostate cancer genetic propensity risk score may modify the association between this tumour and type 2 diabetes mellitus (MCC-Spain study).

Some studies have reported an inverse association between type 2 diabetes mellitus (T2DM) and prostate cancer (PCa), but results on this issue are still inconsistent. In this study, we evaluate whether this heterogeneity might be related to differences in this relationship by tumour or by individual genetic susceptibility to PCa. We studied 1047 incident PCa cases and 1379 randomly selected controls, recruited in 7 Spanish provinces for the population-based MCC-Spain case-control. Tumour were classified by aggressiveness according to the International Society of Urological Pathology (ISUP), and we constructed a PCa polygenic risk score (PRS) as proxy for genetic susceptibility. The epidemiological questionnaire collected detailed self-reported data on T2DM diagnosis and treatment. The association between T2DM status and PCa was studied by fitting mixed logistic regression models, and, for its association by aggressiveness of PCa, with multinomial logistic regression models. To evaluate the possible modulator role of PRS in this relationship, we included the corresponding interaction term in the model, and repeated the analysis stratified by PRS tertiles. Globally, our results showed an inverse association between T2DM and overall PCa limited to grade 1 tumours (ORISUP = 1: 0.72; 95% CI: 0.53-0.98), which could be compatible with a detection bias. However, PCa risk also varied with duration of diabetes treatment -inversely to metformin and positively with insulin-, without differences by aggressiveness. When we considered genetic susceptibility, T2DM was more strongly associated with lower PCa risk in those with lower PRS (ORtertile 1: 0.31; 95% CI: 0.11-0.87), independently of ISUP grade. Our findings reinforce the need to include aggressiveness and susceptibility of PCa, and T2DM treatments in the study of the relationship between both diseases.

Association between genetic variations at 8q24 and prostate cancer risk in Mexican Men.

Variants of 8q24 locus have been associated with prostate cancer (PCa) susceptibility. This study aims to analyze the genetic basis of PCa susceptibility in Mexican men by analyzing SNPs in the 8q24 locus for the first time. A case-control study was performed in 875 men recruited from the Mexican Social Security Institute, 326 patients with PCa, and 549 non-PCa patients (88 with benign prostatic hyperplasia BPH and 461 healthy controls). The 8q24 locus SNPs: rs16901979, rs16983267, rs1447295, and rs7837328 were genotyped by allelic discrimination assays using TaqMan probes. Statistical analysis was performed using Epi Info statistical 7.0 and SNPstats softwares. All genotype frequencies were in Hardy-Weinberg Equilibrium. No differences were observed in genotype distribution between PCa and non-PCa patients for rs6983267. Under different inheritance models, the rs16901979, rs1447295, and rs7837328 SNPs were associated with PCa (OR = 2.8, 1.8, and 1.72, respectively; Pc < 0.001) when comparing PCa patients against controls. This association remains between PCa and BPH patients under different models (OR = 8.5, 2.2, and 1.9, respectively; Pc < 0.001). There were no significant differences in allele and genotype distribution among BPH patients and controls. The combined effect of the alleles CGAA for the SNPs rs16901979, rs6983267, rs1447295, and rs7837328 showed significant differences between PCa patients and controls (OR = 2.9, 95% CI = 1.48-5.83, Pc = 0.008). Four 8q24 variants were not associated with D'Amico score, age at diagnosis, and bone metastases. Our study provides the first confirmation that variants rs16901979, rs1447295, and 7837328 at 8q24 locus are associated with PCa susceptibility in Mexican men.

MicroRNA-1205 Regulation of FRYL in Prostate Cancer.

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors in vivo. To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced in vitro and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.

Initial Findings from a High Genetic Risk Prostate Cancer Clinic

To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men. We are reporting on the first 45 patients enrolled, men between the ages of 35-75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer. Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35-71) and 1.4 ng/ml (range 0.1-11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer. These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

Racial differences in the systemic inflammatory response to prostate cancer.

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.

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 2363: MicroRNA-1205 modulates FRYL/Aurora A kinase protein-protein interaction in prostate cancer cells

Abstract High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs leads to the progression to AR-independent treatment related-neuroendocrine PCa (t-NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with very poor outcomes. PCa neuroendocrine differentiation (PCND) occurs in t-NEPC that is characterized by amplification of Aurora A kinase (AurA). However, the mechanisms that drive t-NEPC are poorly understood. Further understanding PCND in ADT resistance may prevent poorer outcomes. The 8q24 chromosomal locus is an important PCa susceptibility region containing genetic variants associated with increased PCa incidence and aggressiveness. PVT1 is a gene located within this region that encodes microRNA-1205 (miR-1205), whose function is largely unknown. We previously reported miR-1205 underexpression in a cohort of histologically confirmed PCa tissue when compared to normal tissue and that exogenous miR-1205 significantly inhibited tumor growth in CRPC in vivo, suggesting that miR-1205 is a tumor suppressor. To understand the molecular mechanism of miR-1205, we first identfied Fry-like (FRYL) as a direct molecular target of miR-1205. FRYL is predicted to regulate dendritic branching which led us to hypothesize that it is involved in PCND. A Weill Cornell Medicine cohort of 29 benign prostate, 66 localized PCa, 73 CRPC, and 36 NEPC samples whose transcriptome was profiled by RNA-seq, we observed significant overexpression of FRYL in NEPC when compared to localized PCa and benign prostate. After validating FRYL as a target, we examined miR-1205 regulation of FRYL in PCND by culturing LNCaP androgen sensitive PCa cells under androgen deprivation conditions. We observed FRYL mRNA overexpression and significant underexpression of miR-1205 in LNCaP-PCND cells when compared to undifferentiated LNCaP cells. To further characterize this mechanism, miR-1205 was inhibited in RWPE-1 non-tumorigenic and LNCaP cells. As a result, FRYL and AurA protein expression was increased along with NEPC marker expression (Neuron specific enolase 2) when compared to cells transfected with a negative control, suggesting that miR-1205 targets FRYL and AurA to promote PCND. However, RNA pulldown analysis showed that AurA is not a direct target of miR-1205. We observed that FRYL and AurA interaction occurs in LNCaP but not in RWPE-1 cells via co-immunoprecipitation. Interestingly, transfection with miR-1205 mimic inhibits FRYL expression, but not AurA in LNCaP. However, miR-1205 mimic inhibits AurA binding to FRYL. Altogether, these data show that miR-1205 modulates FRYL:AurA protein interaction suggesting that miR-1205 regulation of FRYL:AurA interactions may be important in PCND and t-NEPC. Citation Format: Michelle K. Naidoo, Fayola Levine, Princesca Dorsaint, Andrea Sboner, Olorunseun Ogunwobi. MicroRNA-1205 modulates FRYL/Aurora A kinase protein-protein interaction in prostate cancer cells [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 2363.