Publications by authors named "Jong Y Park"

149 Publications

Novel role of prostate cancer risk variant rs7247241 on PPP1R14A isoform transition through allelic TF binding and CpG methylation.

Hum Mol Genet 2021 Nov 29. Epub 2021 Nov 29.

Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, United States.

Although previous studies identified numerous single nucleotide polymorphisms (SNPs) and their target genes predisposed to prostate cancer (PrCa) risks, SNP-related splicing associations are rarely reported. In this study, we applied distance-based sQTL analysis (sQTLseekeR) using RNA-seq and SNP genotype data from benign prostate tissue (n = 467), and identified significant associations in 3344 SNP-transcript pairs (P ≤ 0.05) at PrCa risk loci. We characterized a common SNP (rs7247241) and its target gene (PPP1R14A) located in chr19q13, a sQTL with risk allele T associated with upregulation of long isoform (P = 9.99E-7). We confirmed the associations in both TCGA (P = 2.42E-24) and GTEX prostate cohorts (P = 9.08E-78). To functionally characterize this SNP, we performed chromatin Immunoprecipitation qPCR and confirmed stronger CTCF and PLAGL2 binding in rs7247241 C than T allele. We found that CTCF binding enrichment was negatively associated with methylation level at the SNP site in human cell lines (r = -0.58). Bisulfite sequencing showed consistent association of rs7247241-T allele with nearby sequence CpG hypermethylation in prostate cell lines and tissues. Importantly, the methylation level at CpG sites nearest to the CTCF binding and first exon splice-in (ψ) of PPP1R14A were significantly associated with aggressive phenotype in the TCGA PrCa cohort. Meanwhile, the long isoform of the gene also promoted cell proliferation. Taken together, with the most updated gene annotations, we reported a set of sQTL associated with multiple traits related to human prostate diseases, and revealed a unique role of PrCa risk SNP rs7247241 on PPP1R14A isoform transition.
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http://dx.doi.org/10.1093/hmg/ddab347DOI Listing
November 2021

Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data: a multi-phased study of prostate cancer.

Cancer Commun (Lond) 2021 Sep 14. Epub 2021 Sep 14.

Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, USA.

Background: DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method.

Methods: Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls.

Results: Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history.

Conclusions: We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.
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http://dx.doi.org/10.1002/cac2.12205DOI Listing
September 2021

SNPxE: SNP-environment interaction pattern identifier.

BMC Bioinformatics 2021 Sep 7;22(1):425. Epub 2021 Sep 7.

Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Background: Interactions of single nucleotide polymorphisms (SNPs) and environmental factors play an important role in understanding complex diseases' pathogenesis. A growing number of SNP-environment studies have been conducted in the past decade; however, the statistical methods for evaluating SNP-environment interactions are still underdeveloped. The conventional statistical approach with a full interaction model with an additive SNP mode tests one specific interaction type, so the full interaction model approach tends to lead to false-negative findings. To increase detection accuracy, developing a statistical tool to effectively detect various SNP-environment interaction patterns is necessary.

Results: SNPxE, a SNP-environment interaction pattern identifier, tests multiple interaction patterns associated with a phenotype for each SNP-environment pair. SNPxE evaluates 27 interaction patterns for an ordinal environment factor and 18 patterns for a categorical environment factor. For detecting SNP-environment interactions, SNPxE considers three major components: (1) model structure, (2) SNP's inheritance mode, and (3) risk direction. Among the multiple testing patterns, the best interaction pattern will be identified based on the Bayesian information criterion or the smallest p-value of the interaction. Furthermore, the risk sub-groups based on the SNPs and environmental factors can be identified. SNPxE can be applied to both numeric and binary phenotypes. For better results interpretation, a heat-table of the outcome proportions can be generated for the sub-groups of a SNP-environment pair.

Conclusions: SNPxE is a valuable tool for intensively evaluate SNP-environment interactions, and the SNPxE findings can provide insights for solving the missing heritability issue. The R function of SNPxE is freely available for download at GitHub ( https://github.com/LinHuiyi/SIPI ).
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http://dx.doi.org/10.1186/s12859-021-04326-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425112PMC
September 2021

Geospatial Cellular Distribution of Cancer-Associated Fibroblasts Significantly Impacts Clinical Outcomes in Metastatic Clear Cell Renal Cell Carcinoma.

Cancers (Basel) 2021 Jul 26;13(15). Epub 2021 Jul 26.

Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point patterns were generated, which were then used to perform spatial analyses using a normalized Ripley's K function at a radius of 25 μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups. Multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) <6 months, and therapy response was defined as PFS >9 months. CAFs exhibited higher cellular clustering with Ki-67 cells than with caspase-3 cells (nK(25): Ki-67 1.19; caspase-3 1.05; = 0.04). The median nearest neighbor (NN) distance from CAFs to Ki-67 cells was shorter compared to caspase-3 cells (15 μm vs. 37 μm, respectively; < 0.001). Multivariable Cox regression analyses demonstrated that both high Ki-67 density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding αSMA+CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT responses. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.
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http://dx.doi.org/10.3390/cancers13153743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345222PMC
July 2021

Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium.

Eur J Epidemiol 2021 Sep 18;36(9):913-925. Epub 2021 Jul 18.

Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, University of Quebec, 531 boul. des Prairies, Laval, QC, H7V 1B7, Canada.

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.
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http://dx.doi.org/10.1007/s10654-021-00781-1DOI Listing
September 2021

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Prostate Cancer Prostatic Dis 2021 Jun 14. Epub 2021 Jun 14.

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.

Materials And Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.

Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.

Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
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http://dx.doi.org/10.1038/s41391-021-00403-7DOI Listing
June 2021

Mindfulness-based stress reduction for breast cancer survivors (MBSR(BC)): evaluating mediators of psychological and physical outcomes in a large randomized controlled trial.

J Behav Med 2021 10 7;44(5):591-604. Epub 2021 May 7.

Moffitt Cancer Center, Tampa, FL, 33612, USA.

MBSR(BC) is known to have a positive impact on psychological and physical symptoms among breast cancer survivors (BCS). The cognitive mechanisms of "how" MBSR(BC) works was addressed in a recent study that found that there was strong consistent evidence that reduced emotional reactivity is a mediator and moderate consistent evidence that mindfulness, rumination, and worry were mediators. The purpose of this study, as part of a larger R01 trial, was to test whether positive effects achieved from the MBSR(BC) program were mediated through changes in increased mindfulness, decreased fear of breast cancer recurrence, and perceived stress. Female BCS > 21 years diagnosed with Stage 0-III breast cancer were randomly assigned to a 6-week MBSR(BC) or a Usual Care (UC)regimen. Potential mediators of 6- and 12-week outcomes were identified by analysis of covariance (ANCOVA), followed by formal mediational analyses of main effects of MBSR(BC) on 6- and 12-week outcomes, including percentage of total effects explained. Among 322 BCS (167 MBSR(BC) and 155 UC), fear of recurrence and perceived stress, but not mindfulness, mediated reductions in anxiety and fatigue at weeks 6 and 12, partially supporting our hypothesis of cognitive mechanisms of MBSR(BC). TRIAL REGISTRATION: Registration Number: NCT01177124 http://www.ClinicalTrials.gov.
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http://dx.doi.org/10.1007/s10865-021-00214-0DOI Listing
October 2021

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

Prostate 2021 Jul 6;81(10):683-693. Epub 2021 May 6.

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).

Methods: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian.

Results: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years.

Conclusions: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.
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http://dx.doi.org/10.1002/pros.24148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491321PMC
July 2021

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 04 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Alcohol Intake and Alcohol-SNP Interactions Associated with Prostate Cancer Aggressiveness.

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Excessive alcohol intake is a well-known modifiable risk factor for many cancers. It is still unclear whether genetic variants or single nucleotide polymorphisms (SNPs) can modify alcohol intake's impact on prostate cancer (PCa) aggressiveness. The objective is to test the alcohol-SNP interactions of the 7501 SNPs in the four pathways (angiogenesis, mitochondria, miRNA, and androgen metabolism-related pathways) associated with PCa aggressiveness. We evaluated the impacts of three excessive alcohol intake behaviors in 3306 PCa patients with European ancestry from the PCa Consortium. We tested the alcohol-SNP interactions using logistic models with the discovery-validation study design. All three excessive alcohol intake behaviors were not significantly associated with PCa aggressiveness. However, the interactions of excessive alcohol intake and three SNPs (rs13107662 [, = 6.2 × 10], rs9907521 [ = 7.1 × 10], and rs11925452 [ = 8.2 × 10]) were significantly associated with PCa aggressiveness. These alcohol-SNP interactions revealed contrasting effects of excessive alcohol intake on PCa aggressiveness according to the genotypes in the identified SNPs. We identified PCa patients with the rs13107662 () AA genotype, the rs11925452 () AA genotype, and the rs9907521 ( AG genotype were more vulnerable to excessive alcohol intake for developing aggressive PCa. Our findings support that the impact of excessive alcohol intake on PCa aggressiveness was varied by the selected genetic profiles.
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http://dx.doi.org/10.3390/jcm10030553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867322PMC
February 2021

Differential DNA Methylation in Prostate Tumors from Puerto Rican Men.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.

In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive ( = 11) and indolent ( = 13) on the basis of the Gleason score were collected. Tumor and adjacent normal tissue were annotated on H&E (Haemotoxylin and Eosin) slides and extracted by macro-dissection. Methylation patterns were assessed using the Illumina 850K DNA methylation platform. Raw data were processed using the Bioconductor package. Global ancestry proportions were estimated using ADMIXTURE (k = 3). One hundred eight genes including were differentially methylated in tumor samples. Regarding the PCa aggressiveness, six hypermethylated genes ( and ) and 11 hypomethylated genes ( and ) were identified. Two significant differentially methylated DNA repair genes, and , were found. Ancestry proportion results for African, European, and Indigenous American were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation patterns related to PCa in H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort for the understanding of PCa in this population.
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http://dx.doi.org/10.3390/ijms22020733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828429PMC
January 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

TMPRSS2-ERG fusion impacts anterior tumor location in men with prostate cancer.

Prostate 2021 02 3;81(2):109-117. Epub 2020 Nov 3.

Dana Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.

Background: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERG ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied.

Methods: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections.

Results: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERG 81.4% vs. ERG 18.6%; p = .005) and EAM (ERG 60.4% vs. ERG 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERG (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERG were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC).

Conclusions: ERG tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.
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http://dx.doi.org/10.1002/pros.24086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810127PMC
February 2021

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

Clin Cancer Res 2021 01 9;27(1):320-329. Epub 2020 Oct 9.

Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institutes, Tampa, Florida.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).

Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.

Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICS) compared with 0 (37.8% vs. 21.9%, = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HR = 2.30; 95% confidence interval (CI), 1.21-4.34; = 0.01] and validation (HR = 2.42; 95% CI, 1.52-3.86; = 0.0001) but not in EAM.

Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042600PMC
January 2021

Influence of gene expression on survival of clear cell renal cell carcinoma.

Cancer Med 2020 11 28;9(22):8662-8675. Epub 2020 Sep 28.

Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Approximately 10%-20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5-year survival is less than 10%. Therefore, significant clinical advances are urgently needed to improve overall survival and patient care to manage the growing number of patients with localized ccRCC. We comprehensively evaluated expression of 388 candidate genes related with survival of ccRCC by using TCGA RNAseq (n = 515), Total Cancer Care (TCC) expression array data (n = 298), and a well characterized Moffitt RCC cohort (n = 248). We initially evaluated all 388 genes for association with overall survival using TCGA and TCC data. Eighty-one genes were selected for further analysis and tested on Moffitt RCC cohort using NanoString expression analysis. Expression of nine genes (AURKA, AURKB, BIRC5, CCNE1, MK167, MMP9, PLOD2, SAA1, and TOP2A) was validated as being associated with poor survival. Survival prognostic models showed that expression of the nine genes and clinical factors predicted the survival in ccRCC patients with AUC value: 0.776, 0.821 and 0.873 for TCGA, TCC and Moffitt data set, respectively. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets. Future studies are warranted to validate these identified genes, determine their biological mechanisms and evaluate their therapeutic potential in preclinical studies.
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http://dx.doi.org/10.1002/cam4.3475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666730PMC
November 2020

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Int J Cancer 2021 01 24;148(1):99-105. Epub 2020 Sep 24.

UMR Inserm 1134 Biologie Intégrée du Globule Rouge, INSERM/Université Paris Diderot-Université Sorbonne Paris Cité/INTS/Université des Antilles, Paris, France.

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.
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http://dx.doi.org/10.1002/ijc.33282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135907PMC
January 2021

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk.

Nat Commun 2020 08 6;11(1):3905. Epub 2020 Aug 6.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.
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http://dx.doi.org/10.1038/s41467-020-17673-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413371PMC
August 2020

TGF-β induced EMT and stemness characteristics are associated with epigenetic regulation in lung cancer.

Sci Rep 2020 06 30;10(1):10597. Epub 2020 Jun 30.

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Transforming growth factor-β (TGF-β) promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT). EMT is often related with acquisition of stemness characteristics. The objective of this study was to determine whether EMT and stemness characteristics induced by TGF-β might be associated with epigenetic regulation in lung cancer. A human normal lung epithelial cell line and four lung cancer cell lines were treated with TGF-β. Transcriptome analysis of BEAS-2B and A549 cells incubated with TGF-β were analyzed through next-generation sequencing (NGS). Western blotting was carried out to investigate expression levels of epithelial and mesenchymal markers. Wound healing and Matrigel invasion assay, sphere formation assay, and in vivo mice tumor model were performed to evaluate functional characteristics of EMT and stemness acquisition. To investigate whether activation of EMT and stem cell markers might be involved in epigenetic regulation of lung cancer, experiment using a DNA methyltransferase inhibitor (5-azacytidine, AZA), methylation-specific PCR (MSP) and bisulfite sequencing were performed. NGS revealed changes in expression levels of EMT markers (E-cadherin, N-cadherin, fibronectin, vimentin, slug and snail) and stem cell markers (CD44 and CD87) in both BEAS-2B and A549 cells. Functional analysis revealed increased migration, invasion, sphere formation, and tumor development in mice after TGF-β treatment. Expression of slug and CD87 genes was activated following treatment with AZA and TGF-β. MSP and bisulfite sequencing indicated DNA demethylation of slug and CD87 genes. These results suggest that TGF-β induced EMT and cancer stemness acquisition could be associated with activation of slug and CD87 gene by their promoter demethylation.
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http://dx.doi.org/10.1038/s41598-020-67325-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326979PMC
June 2020

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1731-1738. Epub 2020 Jun 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483627PMC
September 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Exploring Prostate Cancer Patients' Interest and Preferences for Receiving Genetic Risk Information About Cancer Aggressiveness.

Am J Mens Health 2020 May-Jun;14(3):1557988320919626

Moffitt Cancer Center, Tampa, FL, USA.

The number of cases of aggressive prostate cancer is increasing. Differentiating between aggressive and indolent cases has resulted in increased difficulty for the physician and patient to decide on the best treatment option. Due to this challenge, efforts are underway to profile genetic risk for prostate cancer aggressiveness, which may help physicians and patients at risk for developing aggressive prostate cancer to select an appropriate treatment option. This study explores patients' interest in receiving genetic results, preference for how genetic risk information should be communicated, and willingness to share results with adult male first-degree relatives (FDRs). A nine-item survey was adapted to assess their beliefs and attitudes about genetic testing for prostate cancer aggressiveness. In addition, participants ( = 50) responded to hypothetical scenarios and questions associated with perceived importance of risk disclosure, preferences for receiving genetic risk information, and sharing of results with FDRs. As the hypothetical risk estimate for aggressive prostate cancer increased, patients' willingness to receive genetic risk information increased. This study found that most patients preferred receiving genetic risk education in the form of a DVD (76%), one-page informational sheet (75%), or educational booklet (70%). Almost all patients (98%) reported that they would be willing to share their test results with FDRs. The results of this study highlight prostate cancer patients' desire to receive and share genetic risk information. Future research should focus on assessing the long-term benefits of receiving genetic information for prostate cancer patients and implications of sharing this information with FDRs.
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http://dx.doi.org/10.1177/1557988320919626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243408PMC
June 2021

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
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http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

Multifaceted Function of MicroRNA-299-3p Fosters an Antitumor Environment Through Modulation of Androgen Receptor and VEGFA Signaling Pathways in Prostate Cancer.

Sci Rep 2020 03 20;10(1):5167. Epub 2020 Mar 20.

Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA.

Prostate cancer (PCa) is one of the most common cancers to affect men worldwide. Androgen receptor (AR) signaling is central to PCa and PCa therapy. MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer through modulation of signaling pathways. In the present study, we illustrate the functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissues. Replenishment of miR-299-3p in C4-2B, 22Rv-1 and PC-3 cells contributed to cell cycle arrest, reduced proliferation, migration and increased expression of apoptotic markers. Additionally, overexpression of miR-299-3p induced a reduction of AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in C4-2B cells overexpressing miR-299-3p. miR-299-3p overexpression also inhibited epithelial mesenchymal transition, expression of Slug, TGF-β3, phospho-AKT and phospho-PRAS40, but increased expression of E-cadherin. Furthermore, miR-299 overexpression resulted in reduced tumor growth in xenograft models and increased drug sensitivity. Overall, this study has identified novel mechanisms of antitumor and antimigration function of miR-299-3p through modulation of AR and VEGFA signaling pathways which lead to improved drug sensitivity of PCa.
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http://dx.doi.org/10.1038/s41598-020-62038-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083835PMC
March 2020

Commercial Gene Expression Tests for Prostate Cancer Prognosis Provide Paradoxical Estimates of Race-Specific Risk.

Cancer Epidemiol Biomarkers Prev 2020 01 22;29(1):246-253. Epub 2019 Nov 22.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Commercial gene expression signatures of prostate cancer prognosis were developed and validated in cohorts of predominantly European American men (EAM). Limited research exists on the value of such signatures in African American men (AAM), who have poor prostate cancer outcomes. We explored differences in gene expression between EAM and AAM for three commercially available panels recommended by the National Comprehensive Cancer Network for prostate cancer prognosis.

Methods: A total of 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using NanoString for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. A continuous expression-based risk score was approximated for each. Differential expression, intrapanel coexpression, and risk by race were assessed.

Results: Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, although the magnitudes of expression differences were small. Coexpression patterns were more strongly preserved by race group for Oncotype DX and Decipher than Prolaris. Poorer prognosis was estimated in EAM versus AAM for Oncotype DX ( < 0.001), whereas negligible prognostic differences were predicted between AAM and EAM using Prolaris or Decipher ( > 0.05).

Conclusions: Because of observed racial differences across three commercial gene expression panels for prostate cancer prognosis, caution is warranted when applying these panels in clinical decision-making in AAM.

Impact: Differences in gene expression by race for three commercial panels for prostate cancer prognosis indicate that further study of their effectiveness in AAM with long-term follow-up is warranted.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942810PMC
January 2020

Aptamer Selection for Detecting Molecular Target Using Cell-SELEX (Systematic Evolution of Ligands by Exponential Enrichment) Technology.

Methods Mol Biol 2019 ;2054:223-241

Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.

Cell-SELEX is a live cell-based in vitro selection method that generates functional oligonucleotides, or aptamers. Often referenced as the chemist's antibody, aptamers bind to select targets with high affinity and can be utilized in a number of applications, including biomedicine, bioimaging, and biosensing. Here we describe the cell-SELEX technique and discuss this methodology's unique merit(s)-namely the ability to isolate highly selective aptamer panels with no prior knowledge of cellular signatures. This strategy thus presents as a technology that has the potential to enhance the precision of molecular medicine and targeted therapeutics.
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http://dx.doi.org/10.1007/978-1-4939-9769-5_15DOI Listing
June 2020
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