Prostate Cancer Susceptibility Loci Research Articles

Genetic Polymorphisms of the Telomerase Reverse Transcriptase Gene in Relation to Prostate Tumorigenesis, Aggressiveness and Mortality: A Cross-Ancestry Analysis.

Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12-1.20, p = 4.12 × 10-16) and rs11291391 (OR = 1.73, 95%CI:1.34-2.25, p = 3.04 × 10-5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31-1.71, p = 2.91 × 10-9) and rs2853677 (OR = 1.74, 95%CI:1.52-1.98, p = 3.52 × 10-16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04-2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10-15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171). TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries.

How Well do Polygenic Risk Scores Identify Men at High Risk for Prostate Cancer? Systematic Review and Meta-Analysis.

Genome-wide association studies have revealed over 200 genetic susceptibility loci for prostate cancer (PCa). By combining them, polygenic risk scores (PRS) can be generated to predict risk of PCa. We summarize the published evidence and conduct meta-analyses of PRS as a predictor of PCa risk in Caucasian men. Data were extracted from 59 studies, with 16 studies including 17 separate analyses used in the main meta-analysis with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases. Random effects meta-analysis was used to obtain pooled estimates of area under the receiver-operating characteristic curve (AUC). Meta-regression was used to assess the impact of number of single-nucleotide polymorphisms (SNPs) incorporated in PRS on AUC. Heterogeneity is expressed as I2 scores. Publication bias was evaluated using funnel plots and Egger tests. The ability of PRS to identify men with PCa was modest (pooled AUC 0.63, 95% CI 0.62-0.64) with moderate consistency (I2 64%). Combining PRS with clinical variables increased the pooled AUC to 0.74 (0.68-0.81). Meta-regression showed only negligible increase in AUC for adding incremental SNPs. Despite moderate heterogeneity, publication bias was not evident. Typically, PRS accuracy is comparable to PSA or family history with a pooled AUC value 0.63 indicating mediocre performance for PRS alone.

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.

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 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) > 0.01) genotyped and imputed variants (r2 > 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<0.05) associated with prostate cancer risk with directionally consistent effect estimates, of which 44 reached the genome-wide significance (P<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 < 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.

Genetic variants in the cholesterol biosynthesis pathway genes and risk of prostate cancer.

Previous studies have found the relationship between cholesterol biosynthesis pathway genes and the risk or prognosis of prostate cancer (PCa), while there is no definite evidence that genetic variants in the cholesterol biosynthesis pathway gene is related to PCa risk. Consequently, we performed this study to explore the associations of single-nucleotide polymorphisms (SNPs) in the cholesterol biosynthesis pathway with PCa risk. We systematically evaluated the association of SNPs in 21 cholesterol biosynthesis pathway genes with the risk of PCa using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial database using a logistic regression model. Gene expression data of PCa from Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database were applied for mRNA expression analysis. The TCGA database was used to perform expression quantitative trait loci (eQTL) analysis. The interaction between demographic factors and SNPs was analyzed using two-by-four tables. We found T allele of rs67415672 in HMGCS1 is a significant protective allele of PCa [adjusted odds ratio (OR)=0.90, 95% confidence interval (CI)=0.83-0.97, P=4.16×10-3]. Moreover, rs67415672 was an eQTL for HMGCS1 (P=2.23×10-6). The expression of HMGCS1 significantly decreased in PCa primary tumors than that in normal tissues. These findings indicated that the HMGCS1 rs67415672 might be possible functional susceptibility loci for PCa.

Abstract 3513: Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population

Abstract Background: Prostate cancer (PC) is the second most common cancer in men worldwide with a rising prevalence. However, only limited number of clinically actionable variants are known. The objective of this study is to identify novel PC susceptibility loci with potential clinical relevance utilizing the increased genetic drift and reduced selective pressure of the recently bottlenecked powerful resource of the Finnish population. Methods: We meta-analysed >185.000 germline single nucleotide polymorphisms (SNPs) in 2738 PC cases and 2401 controls of Finnish origin in the Collaborative Oncological Gene-Environment Study (COGS) using Illumina iSelect custom SNP genotyping platform. Results: Altogether 160 variants remain significant on GWAS level (p<5 × 10−8) in 18 different gene regions. Out of the 160 identified PC susceptibility hits 78 (49%) are novel variants not reported earlier in association with PC. PC associated signals are in close proximity to one another forming genetic hot-spots on chromosomes 8, 7, 11, 17 and 19. The strength of association varies for 101 PC risk variants (OR 1.24-1.86) and 59 protective SNPs (OR 0.59-0.80). The strongest risk gene is CASC8 (OR=1.86; p=1.214 × 10−11). The most significant signals were found at the 8p21.2 chromosomal region (p<7.6 × 10−16). Functional annotation identified a missense coding SNP at KLK3 gene to be a candidate causal variant. We showed evidence for association both with early-onset PC (OR 1.73; P=0.02), high serum PSA level at diagnosis (OR 1.36; P=0.024) and with aggressive PC (Gleason score ≥8; OR 1.44; P=0.02) at 17q21. Conclusion: The results facilitate risk stratification for screening, clinical studies, treatment choices and functional research of PC Citation Format: Csilla Sipeky, Teuvo L. Tammela, Anssi Auvinen, Johanna Schleutker. Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3513.

Abstract PR06: Research on prostate cancer in men of African ancestry: Defining the roles of genetics, tumor markers, and social stress

Abstract African American men have a >60% higher incidence and are more likely to be diagnosed with aggressive prostate cancer than white men. The reasons are not clear but are likely to include a multitude of factors such as social factors (e.g., lifetime stress), inherited susceptibility, and tumor-related features such as somatic alterations and local inflammation in the microenvironment. To investigate these hypotheses, over the next five years, we will establish a large, national, population-based cohort study, RESPOND (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Tumor Markers and Social Stress) of 10,000 African American men with incident prostate cancer identified through nine U.S. cancer registries from states that include 38% of all African American prostate cancer cases in the U.S. We will also recruit men who wish to volunteer through our website (RespondStudy.org). The cohort will provide comprehensive information on 1) multilevel stressors over the lifecourse; 2) geographic data on residential segregation, and social and built environmental factors; 3) lifestyle factors and health behaviors; 4) disease-specific factors including PSA screening history and treatment choice; 5) germline DNA to study genetic susceptibility; and 6) tumor samples to study somatic changes associated with aggressive disease. No previous study has attempted to obtain information across these domains in a single large cohort in order to understand the independent and joint contributions of these factors. Leveraging the RESPOND resource and investigator expertise, we have designed a research program composed of four Projects that are supported by four Cores, which are all focused on the central theme of identifying social and biologic factors related to prostate cancer disease aggressiveness in African American men. These Projects include the investigation of multilevel social stressors across the lifecourse in relationship with aggressive prostate cancer (Project 1); genome-wide discovery efforts of germline susceptibility loci for aggressive prostate cancer and examination of the relationship between germline and somatic variation (Project 2); the identification of underlying somatic alterations in prostate cancer tumors and biologic pathways that are related to aggressive disease (Project 3); and a detailed assessment of inflammation in the tumor microenvironment as it relates to prostate cancer aggressiveness (Project 4). Each of the four Projects addresses a distinct research domain, but together they will provide a comprehensive picture of the major factors that contribute to aggressive prostate cancer in African American men. The information we will discover is likely to help in explaining prostate cancer health disparities and have immediate clinical implications in the areas of improved patient stratification and personalized medicine for African American men. This abstract is also being presented as Poster C058. Citation Format: Ann S. Hamilton, Scarlett Gomez, Xiao-Cheng Wu, Kevin Ward, Melissa Bondy, Rosemary Cress, Jennifer Beebe-Dimmer, Karen Pawlish, Jong Park, Iona Cheng, Antoinette Stroup, Thomas Sellers, Susan Gundell, Angelo Demarzo, Denise Modjeski, Stephen Chanock, Salma Shariff-Marco, Mindy DeRouen, John Carpten, Franklin Huang, Karen Sfanos, Tamara Lotan, David Conti, Christopher Haiman. Research on prostate cancer in men of African ancestry: Defining the roles of genetics, tumor markers, and social stress [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR06.

12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population

Genome-wide association studies (GWAS) have identified ~170 genetic loci associated with prostate cancer (PCa) risk, but most of them were identified in European populations. We here performed a GWAS and replication study using a large Japanese cohort (9,906 cases and 83,943 male controls) to identify novel susceptibility loci associated with PCa risk. We found 12 novel loci for PCa including rs1125927 (TMEM17, P = 3.95 × 10−16), rs73862213 (GATA2, P = 5.87 × 10−23), rs77911174 (ZMIZ1, P = 5.28 × 10−20), and rs138708 (SUN2, P = 1.13 × 10−15), seven of which had crucially low minor allele frequency in European population. Furthermore, we stratified the polygenic risk for Japanese PCa patients by using 82 SNPs, which were significantly associated with Japanese PCa risk in our study, and found that early onset cases and cases with family history of PCa were enriched in the genetically high-risk population. Our study provides important insight into genetic mechanisms of PCa and facilitates PCa risk stratification in Japanese population.

Single-Nucleotide Polymorphisms Sequencing Identifies Candidate Functional Variants at Prostate Cancer Risk Loci.

Genome-wide association studies have identified over 150 risk loci that increase prostate cancer risk. However, few causal variants and their regulatory mechanisms have been characterized. In this study, we utilized our previously developed single-nucleotide polymorphisms sequencing (SNPs-seq) technology to test allele-dependent protein binding at 903 SNP sites covering 28 genomic regions. All selected SNPs have shown significant cis-association with at least one nearby gene. After preparing nuclear extract using LNCaP cell line, we first mixed the extract with dsDNA oligo pool for protein–DNA binding incubation. We then performed sequencing analysis on protein-bound oligos. SNPs-seq analysis showed protein-binding differences (>1.5-fold) between reference and variant alleles in 380 (42%) of 903 SNPs with androgen treatment and 403 (45%) of 903 SNPs without treatment. From these significant SNPs, we performed a database search and further narrowed down to 74 promising SNPs. To validate this initial finding, we performed electrophoretic mobility shift assay in two SNPs (rs12246440 and rs7077275) at CTBP2 locus and one SNP (rs113082846) at NCOA4 locus. This analysis showed that all three SNPs demonstrated allele-dependent protein-binding differences that were consistent with the SNPs-seq. Finally, clinical association analysis of the two candidate genes showed that CTBP2 was upregulated, while NCOA4 was downregulated in prostate cancer (p < 0.02). Lower expression of CTBP2 was associated with poor recurrence-free survival in prostate cancer. Utilizing our experimental data along with bioinformatic tools provides a strategy for identifying candidate functional elements at prostate cancer susceptibility loci to help guide subsequent laboratory studies.

The X-linked tumor suppressor TSPX downregulates cancer-drivers/oncogenes in prostate cancer in a C-terminal acidic domain dependent manner.

TSPX is a tumor suppressor gene located at Xp11.22, a prostate cancer susceptibility locus. It is ubiquitously expressed in most tissues but frequently downregulated in various cancers, including lung, brain, liver and prostate cancers. The C-terminal acidic domain (CAD) of TSPX is crucial for the tumor suppressor functions, such as inhibition of cyclin B/CDK1 phosphorylation and androgen receptor transactivation. Currently, the exact role of the TSPX CAD in transcriptional regulation of downstream genes is still uncertain. Using different variants of TSPX, we showed that overexpression of either TSPX, that harbors a CAD, or a CAD-truncated variant (TSPX[∆C]) drastically retarded cell proliferation in a prostate cancer cell line LNCaP, but cell death was induced only by overexpression of TSPX. Transcriptome analyses showed that TSPX or TSPX[∆C] overexpression downregulated multiple cancer-drivers/oncogenes, including MYC and MYB, in a CAD-dependent manner and upregulated various tumor suppressors in a CAD-independent manner. Datamining of transcriptomes of prostate cancer specimens in the Cancer Genome Atlas (TCGA) dataset confirmed the negative correlation between the expression level of TSPX and those of MYC and MYB in clinical prostate cancer, thereby supporting the hypothesis that the CAD of TSPX plays an important role in suppression of cancer-drivers/oncogenes in prostatic oncogenesis.

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

7 - Novel susceptibility loci for prostate cancer identified by genome-wide association and replication study

7 - Novel susceptibility loci for prostate cancer identified by genome-wide association and replication study

Mutational Profile of Aggressive, Localised Prostate Cancer from African Caribbean Men Versus European Ancestry Men

Causes of high mortality of prostate cancer in men of African ancestry living in the French West Indies are still debated, between suspicions of environmental factors and genetic susceptibility. We report an integrated genomic study of 25 tumour tissues from radical prostatectomy of aggressive (defined by International Society of Urological Pathology ≥3) prostate cancer patients (10 African Caribbean and 15 French Caucasian) using single nucleotide polymorphism arrays, whole-genome sequencing, and RNA sequencing. The results show that African Caribbean tumours are characterised by a more frequent deletion at 1q41-43 encompassing the DNA repair gene PARP1, and a higher proportion of intrachromosomal rearrangements including duplications associated with CDK12 truncating mutations. Transcriptome analyses show an overexpression of genes related to androgen receptor activity in African Caribbean tumours, and of PVT1, a long non-coding RNA located at 8q24 that confirms the strong involvement of this region in prostate tumours from men of African ancestry.Patient summary: Mortality of prostate cancer is higher in African Caribbean men than in French Caucasian men. Specificities of the former could be explained by genomic events linked with key genes such as DNA damage pathway genes PARP1, CDK12, and the oncogenic long non-coding RNA gene PVT1 at the 8q24 prostate cancer susceptibility locus.

Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus

Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressiveprostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic.

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

MP70-09 IDENTIFICATION OF NINE NEW SUSCEPTIBILITY LOCI FOR PROSTATE CANCER IN THE JAPANESE POPULATION

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2018MP70-09 IDENTIFICATION OF NINE NEW SUSCEPTIBILITY LOCI FOR PROSTATE CANCER IN THE JAPANESE POPULATION Ryo Takata, Shusuke Akamatsu, Hidewaki Nakagawa, Naoki Terada, Yoichiro Kato, Mitsugu Kanehira, Jun Sugimura, So Omori, Takaya Abe, Johji Inazawa, Osamu Ogawa, and Wataru Obara Ryo TakataRyo Takata More articles by this author , Shusuke AkamatsuShusuke Akamatsu More articles by this author , Hidewaki NakagawaHidewaki Nakagawa More articles by this author , Naoki TeradaNaoki Terada More articles by this author , Yoichiro KatoYoichiro Kato More articles by this author , Mitsugu KanehiraMitsugu Kanehira More articles by this author , Jun SugimuraJun Sugimura More articles by this author , So OmoriSo Omori More articles by this author , Takaya AbeTakaya Abe More articles by this author , Johji InazawaJohji Inazawa More articles by this author , Osamu OgawaOsamu Ogawa More articles by this author , and Wataru ObaraWataru Obara More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2253AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer (PC) is one of the most common malignancies in males throughout the world. Although the mechanisms by which prostate cancer develops and progresses are not clear, there is considerable evidence that genetic factors are important in its etiology. Recent genome-wide association studies (GWAS) have identified common variants at multiple loci that have moderate effects on PC risk. However, GWAS for prostate cancer have been undertaken exclusively among European populations. Further GWAS of Asian and other ethnic populations are required to identify additional susceptibility loci for PC and to enhance the understanding of the complex genetic effect on prostate carcinogenesis. To identify genetic factors that confer risk of PC in the Japanese population, we carried out extensive GWAS using Japanese case and controls. METHODS We carried out a genome-wide association study of 511,810 SNPs using 5,088 Japanese men with PC and 10,682 healthy control subjects. We obtained 7,521,072 SNPs information by imputation using 1000 Genomes Project data. In addition, we conducted replication study in an independent set of 4,818 Japanese PC patients and 73,261 control subjects. RESULTS From the 108 associated SNPs reported in previous GWAS, we confirmed the association of 49 SNPs at P < 0.05 in the Japanese population. The remaining 59 SNPs showed no association (P > 0.05). Therefore, it became evident that the SNPs associated with PC pathogenesis greatly varies depending on race. In addition, we performed replication study for 101 SNPs which indicated P < 1.0 x 10-5 in the GWAS. As a result, we identified nine new loci for PC susceptibility at 1p36, 8q24, 10q22, 12p13, 12q21, 15q22, 20p13 and 22q13 (P = 3.34 x 10-8 - 5.28 x 10-20). Moreover, the polymorphisms of SNP and the expression of the surrounding gene showed a significant correlation with QTL analysis in the 2 associated SNPs. CONCLUSIONS This study had an advantage of eliminating of affect for genetic heterogeneity, since we conducted GWAS using genetically quite a homogeneous population of Japanese. These findings advance our understanding of the genetic basis of prostate carcinogenesis and highlight the genetic heterogeneity of PC susceptibility among different ethnic populations. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e937 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Ryo Takata More articles by this author Shusuke Akamatsu More articles by this author Hidewaki Nakagawa More articles by this author Naoki Terada More articles by this author Yoichiro Kato More articles by this author Mitsugu Kanehira More articles by this author Jun Sugimura More articles by this author So Omori More articles by this author Takaya Abe More articles by this author Johji Inazawa More articles by this author Osamu Ogawa More articles by this author Wataru Obara More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Validation of the novel susceptibility loci for prostate cancer in a Chinese population.

The present study evaluated 23 newly identified susceptibility loci for prostate cancer (PCa) in a Chinese population and assessed whether any validated loci were associated with the genetic risk score (GRS) of PCa in a Chinese population. A total of 1,417 patients with PCa and 1,008 controls were recruited in the present study. The association of each single nucleotide polymorphism (SNP) with PCa risk and PCa aggressiveness was analyzed. The predictive ability of two GRSs based on 30 SNPs (GRS30) and the 9 most significant SNPs (GRS9) in the Chinese population were also compared. Among the 19 SNPs evaluated, 1 SNP (rs7153648 at 14q23) was associated with PCa risk [odds ratio (OR)=1.206, P<0.05)] and 1 SNP (rs636291 at 1p23) was associated with PCa aggressiveness (OR=1.123, P<0.05). GRS30 and GRS9 were significantly increased in patients with PCa compared with that among non-PCa controls. The areas under receiver operating characteristic curves of GRS9 and GRS 30 were similar (0.792 for GRS9 vs. 0.7994 for GRS30, P=0.138). To conclude, among the 19 SNPs evaluated, only 1 SNP was associated with PCa risk in the Chinese population. SNPs that were weakly associated with PCa were unlikely to improve the predictive ability of existing GRS in the Chinese population.

Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci.

Large-scale genome-wide association studies have identified multiple single-nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to cis-acting associations due to study limitations. While trans-eQTL scans suffer from high testing dimensionality, recent evidence indicates most trans-eQTL associations are mediated by cis-regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive cis-mediator analysis using RNA-Seq data from 471 normal prostate tissue samples to identify downstream regulatory associations of previously identified prostate cancer risk variants. We discovered multiple trans-eQTL associations that were significantly mediated by cis-regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor HNF1B, and target trans-genes with known HNF response elements (MIA2, SRC, SEMA6A, KIF12). We additionally identified evidence of cis-acting down-regulation of MSMB via rs10993994 corresponding to reduced co-expression of NDRG1. The majority of these cis-mediator relationships demonstrated trans-eQTL replicability in 87 prostate tissue samples from the Gene-Tissue Expression Project. These findings provide further biological context to known risk loci and outline new hypotheses for investigation into the etiology of prostate cancer.