Risk Of Aggressive Prostate Cancer Research Articles

DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis.

Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP−/− mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.

Lifestyle and dietary factors in relation to prostate cancer risk

The aim of the present study was to determine the association between the socio-demographic, lifestyle factors, and dietary habits with the risk of prostate cancer (PC) in a case–control study of Spanish men. None of the socio-demographic, lifestyle or dietetic variables was found predictors of PC risk. Body mass index was associated with an increased risk for aggressive PC and fruit consumption with lower Gleason scores, thus less aggressive cancers. Nonetheless, after applying Bonferroni correction, these variables were not still associated with PC aggressiveness. More adequately, powered epidemiological studies that measure the effect of lifestyle and dietary intake in PC risk and aggressiveness are warranted to further elucidate the role of these modifiable factors on PC etiology.

ABO blood group alleles and prostate cancer risk: Results from the breast and prostate cancer cohort consortium (BPC3).

ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer. We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score ≥8 or locally advanced/metastatic disease (stage T3/T4/N1/M1). We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95%CI = 0.87-1.08; Type B: OR = 0.92, 95%CI =n0.77-1.09; Type AB: OR = 1.25, 95%CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk. ABO blood type was not associated with risk of aggressive prostate cancer.

The HDL receptor SR-BI is associated with human prostate cancer progression and plays a possible role in establishing androgen independence.

BackgroundHuman prostate cancer represents one of the most frequently diagnosed cancers in men worldwide. Currently, diagnostic methods are insufficient to identify patients at risk for aggressive prostate cancer, which is essential for early treatment. Recent data indicate that elevated cholesterol levels in the plasma are a prerequisite for the progression of prostate cancer. Here, we analyzed clinical prostate cancer samples for the expression of receptors involved in cellular cholesterol uptake.MethodsWe screened mRNA microarray files of prostate cancer samples for alterations in the expression levels of cholesterol transporters. Furthermore, we performed immunohistochemistry analysis on human primary prostate cancer tissue sections derived from patients to investigate the correlation of SR-BI with clinicopathological parameters and the mTOR target pS6.ResultsIn contrast to LDLR, we identified SR-BI mRNA and protein expression to be induced in high Gleason grade primary prostate cancers. Histologic analysis of prostate biopsies revealed that 53.6 % of all cancer samples and none of the non-cancer samples showed high SR-BI staining intensity. The disease-free survival time was reduced (P = 0.02) in patients expressing high intra-tumor levels of SR-BI. SR-BI mRNA correlated with HSD17B1 and HSD3B1 and SR-BI protein staining showed correlation with active ribosomal protein S6 (RS = 0.828, P < 0.00001).ConclusionsWe identified SR-BI to indicate human prostate cancer formation, suggesting that increased levels of SR-BI may be involved in the generation of a castration-resistant phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0087-z) contains supplementary material, which is available to authorized users.

Abstract 936: Serum lipid metabolites and alpha-ketoglutarate are inversely associated with aggressive prostate cancer

Abstract Background: There are very few well-established risk factors for prostate cancer. Metabolomic profiling of blood represents an agnostic approach with the potential to identify biomarkers associated with risk. We previously identified several circulating lipid and energy metabolism-related compounds (e.g., alpha-ketoglutarate; AKG) that were altered in men who later developed prostate cancer. Our aim here was to determine the extent to which those findings replicated in a larger study, and whether new metabolite signals could be uncovered. Methods: We conducted a prospective prostate cancer case-control analysis nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort, and sampled 200 cases (100 aggressive and 100 non-aggressive), matching one control to each based on age and date of baseline fasting serum collection. Median time from serum collection to prostate cancer diagnosis was 10 years (range, 1-20). Sera were analyzed on a high resolution accurate mass (HRAM) platform of ultrahigh performance liquid chromatography/mass spectroscopy (LC-MS) and gas chromatography/mass spectroscopy (GC-MS) (Metabolon, Inc.) that identified 654 known metabolites. Over- and under-representation of metabolite classes among our top metabolite signals was tested using the Fisher's exact test for metabolites jointly classified as having a p-value &amp;lt;0.05 (Y/N) and as belonging to a specific chemical class (Y/N). For each metabolite, we used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) of risk associated with a one standard deviation increment in metabolite concentration. Results: Of the 32 metabolites associated with aggressive prostate cancer at p&amp;lt;0.05, 22 were lipids, which as a metabolite class was strongly associated with aggressive but not non-aggressive prostate cancer risk (p = 3.1 × 10−4 and p = 0.10, respectively) (20 of the 22 lipids were inversely associated with aggressive disease risk). Inositol-1-phosphate and oleoyl-linoleoyl-glycerophosphoinositol-1 were the two strongest metabolite signals for aggressive prostate cancer (OR 0.55, 95% CI 0.37-0.80, p = 0.002; and, OR 0.64, 95% CI 0.47-0.87, p = 0.004, respectively). The AKG association of our earlier study was replicated in the present analysis (OR 0.65, 95% CI 0.47-0.91, p = 0.011). Some steroid and thyroid hormones were positively associated with both aggressive and non-aggressive prostate cancer. Conclusion: In this prospective study, serum lipid metabolites were inversely associated with risk of aggressive prostate cancer, including particularly inositol-1-phosphate and oleoyl-linoleoyl-glycerophosphoinositol-1, and the data confirm our previous finding that men with higher AKG were less likely to develop aggressive prostate cancer. A role for altered energy and lipid metabolism in the pathogenesis of aggressive prostate cancer is implicated. Citation Format: Alison Mondul, Steven Moore, Joshua Sampson, Stephanie Weinstein, Demetrius Albanes. Serum lipid metabolites and alpha-ketoglutarate are inversely associated with aggressive prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2015-936

Polymorphisms In The Nitric-Oxide Synthase 2 Gene And Prostate Cancer Pathogenesis

Nitric-oxide synthase (NOS)-polymorphisms influence the cellular amount of NO, and are associated with disease-risk in many disorders. We investigated 145 SNP-polymorphisms and a (CCTTT)n-microsatellite in the NOS2-gene in 3161 prostate-cancer patients and 2149 controls from a Swedish population-based GWAS-study. To analyze possible associations between NOS2-polymorphisms, prostate cancer, and prostate cancer pathogenesis. Two groups were analyzed, those with advanced tumours (Gleason≥6), and those with tumours of mixed Gleason-statues. Affymetrix 5.0-chip (SNP-polymorphisms), DNA Fragment-analysis and Sequencing ((CCTTT)n-microsatellite) were used for genotyping. Genotypes were combined with information on tumour stage, Gleason, PSA, metastases and cancer-specific death, using clinical follow-up. We divided the (CCTTT)n-alleles into short (S, n≤10), intermediate (M, n=11-12) and long (L, n≥13). Patients homozygous for longer repeats (LL) had decreased risk of highly aggressive (Gleason ≥7;PSA>20;T3+) tumours (OR:0.40;CI:0.14-1.08;p=0.071), but, once ill they showed a threefold increased risk of dying in prostate cancer (HR:3.31;CI:0.85-12.85;p=0.084), compared to SS-homozygotes. The SNP-alleles that co-varied with the (CCTTT)l-allele also had lower risk of aggressive tumours, as well as, once ill, a 2-4 times higher risk of dying (p=0.009). Also the proportion of patients with lymph node metastases increased with length of the (CCTTT)n-alleles of the patients (SS<SM<SL<MM<ML <LL)(trend analysis; p=0.033). Nitric oxide can induce proliferation as well as apoptosis depending on cellular context. Our results suggest that NOS2 polymorphisms may influence the risk of aggressive prostate cancer and that these polymorphisms could have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.

Abstract 5569: p73 dinucleotide polymorphism genotyping of human cancer cell lines

Abstract The p73 gene is a member of the p53 tumor suppressor family. The p73 dinucleotide polymorphism (DNP) (rs1801173) is a G4C14-to-A4T14 linked pair of transitions located in exon 2 between the P1 and P2 gene promoters. The P1 and P2 p73 gene promoters are the transcription initiation sites for mRNAs encoding TAp73 and ΔNp73 isoforms, respectively. Recently, we reported the p73 DNP allele was associated with (1) decreased risk [OR = 0.55, 95%CI = 0.31-0.99] for aggressive prostate cancer (PCa) and (2) increased TAp73/ΔNp73 protein isoform ratios in ten human cancer cell lines. We hypothesize the presence of the p73 DNP allele causes altered p73 promoter usage resulting in increased TAp73/ΔNp73 protein isoform ratios, which could explain the observed decreased risk for PCa aggressiveness. Our ultimate goal is to assess the potential of p73 DNP as a biomarker for lower aggressive PCa risk. Therefore, our initial aim in this study was to determine the p73 DNP genotype in ten additional human cancer cell lines (DU 145, JEG-3, K-562, LNCaP, MDA-MB-231, MDA-MB-468, MRC-5, PC-3, SW48 and U-2OS) not yet characterized for p73 DNP status. We previously reported the p73 DNP genotype of three human cancer cell lines that we used as genotyping controls: Caco-2 (homozygous polymorphic), NCI-H1299 (homozygous wild type), and HepG2 (heterozygous). Cell lines were cultured and genomic DNA was isolated and quantitated. Cell line genomic DNA samples were used in TaqMan Real Time-PCR allelic discrimination assays to determine the p73 DNP genotypes. Our data conclusively determined that DU 145, JEG-3, K-562, LNCaP, MDA-MB-468, MRC-5, SW48 and U-2OS were p73 DNP homozygous wild type, while PC-3 and MDA-MB-231 werw p73 DNP heterozygous. Cell Line p73 DNP GenotypesCELL LINE NAMEP73 DNP GENOTYPEDU145CCJEG-3CCK-562CCLNCaPCCMDA-MB-231CTMDA-MB-468CCMRC-5CCPC-3CTSW48CCU-2OSCC Citation Format: L. Michael Carastro, Kaia K. Hampton, Ricardo A. Cordova Estupinan, Hyun Y. Park, Dongwha Kim, Jong Y. Park. p73 dinucleotide polymorphism genotyping of human cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2015-5569

A Family History of Lethal Prostate Cancer and Risk of Aggressive Prostate Cancer in Patients Undergoing Radical Prostatectomy.

We investigated whether a family history of lethal prostate cancer (PCa) was associated with high-risk disease or biochemical recurrence in patients undergoing radical prostatectomy. A cohort of radical prostatectomy patients was stratified into men with no family history of PCa (NFH); a first-degree relative with PCa (FH); and those with a first-degree relative who had died of PCa (FHD). Demographic, operative and pathologic outcomes were analyzed. Freedom from biochemical recurrence was examined using Kaplan-Meier log rank. A multivariate Cox logistic regression analysis was also performed. We analyzed 471 men who underwent radical prostatectomy at our institution with known family history. The three groups had: 355 patients (75%) in NFH; 97 patients (21%) in FH; and 19 patients (4%) in FHD. The prevalence of a Gleason score ≥8, higher pathologic T stage, and biochemical recurrence (BCR) rates did not significantly differ between groups. On Kaplan-Meier analysis there were no differences in short-term BCR rates (p = 0.212). In this cohort of patients undergoing radical prostatectomy, those with first-degree relatives who died of PCa did not have an increased likelihood of high-risk or aggressive PCa or shorter-term risk of BCR than those who did not.

Genotyping of a p73 Dinucleotide Polymorphism in Human Cancer Cell Lines

The p73 gene is a member of the p53 tumor suppressor family. A p73 dinucleotide polymorphism (DNP) (rs1801173) is a G4C14‐to‐A4T14 linked pair of transitions located in exon 2 and lies between the P1 and P2 gene promoters. The P1 and P2 p73 gene promoters are the transcription initiation sites for mRNAs encoding TAp73 and DNp73 isoforms, respectively. Recently, we reported the p73 DNP allele was associated with (1) decreased risk [OR = 0.55, 95%CI =0.31‐0.99] for aggressive prostate cancer (PCa) and (2) increased TAp73/DNp73 protein isoform ratios in ten human cancer cell lines. We hypothesize the presence of the p73 DNP allele causes altered p73 promoter usage, ultimately resulting in increased TAp73/DNp73 protein isoform ratios, which could explain the observed decreased risk for PCa aggressiveness. Our ultimate goal is to assess the potential of p73 DNP as a biomarker for lower aggressive PCa risk. Therefore, our initial goal in this study was to determine the p73 DNP genotype in four human cancer cell lines (DU 145, MDA‐MB‐468, PC‐3 and SW48) not yet characterized for p73 DNP status. We previously characterized the p73 DNP genotype of three human cancer cell lines that we used as genotyping controls: Caco‐2 (homozygous polymorphic), NCI‐H1299 (homozygous wild type), and HepG2 (heterozygous). These seven cell lines were cultured and genomic DNA was isolated and quantitated. Cell line genomic DNA samples were used in TaqMan Real Time‐PCR allelic discrimination assays to determine the p73 DNP genotypes. Our data conclusively determined that DU 145, MDA‐MB‐468, and SW48 were p73 DNP homozygous wild type, and PC‐3 was p73 DNP heterozygous.

MP77-20 AMONG MEN WITH LOW-GRADE PROSTATE CANCER ON PROSTATE BIOPSY, THE 4KSCORE PREDICTS MORE AGGRESSIVE PROSTATE CANCER AT PROSTATECTOMY.

You have accessJournal of UrologyProstate Cancer: Detection and Screening VI1 Apr 2015MP77-20 AMONG MEN WITH LOW-GRADE PROSTATE CANCER ON PROSTATE BIOPSY, THE 4KSCORE PREDICTS MORE AGGRESSIVE PROSTATE CANCER AT PROSTATECTOMY. Sanoj Punnen, Stephen Zappala, Dan Sjoberg, Vinita Mathur, Michael Reeve, and Dipen Parekh Sanoj PunnenSanoj Punnen More articles by this author , Stephen ZappalaStephen Zappala More articles by this author , Dan SjobergDan Sjoberg More articles by this author , Vinita MathurVinita Mathur More articles by this author , Michael ReeveMichael Reeve More articles by this author , and Dipen ParekhDipen Parekh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.560AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Most men diagnosed with prostate cancer in the United States are found to have low-grade tumors. While many of these men are good candidates for active surveillance, a proportion will have a bad outcome due to the presence of a more aggressive prostate cancer that was missed on initial biopsy. A recent prospective study confirmed the 4Kscore accurately predicts the likelihood of aggressive cancer on prostate biopsy. We wanted to see if the 4Kscore could predict the presence of more significant cancer in a population of men with low-grade tumors on the diagnostic biopsy. METHODS A recent large prospective trial enrolled 1012 men referred for prostate biopsy for suspicion of prostate cancer from 26 sites throughout the United States. We selected men who were found to have low-grade (Gleason 6) cancer on biopsy for this analysis. The 4Kscore calculates the risk of aggressive prostate cancer on prostate biopsy by a blood test that measures levels of four kallikrein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-2) plus age, DRE findings, and prior biopsy status. We investigated whether the 4Kscore was associated with more significant cancer among men found to have Gleason 6 cancer on prostate biopsy. We also looked at a subset of these men who underwent radical prostatectomy to see if the 4Kscore was associated with prostate cancer being upgraded in the surgical specimen. RESULTS Among the 1012 men enrolled in this trial, 239 men were found to have Gleason 6 cancer on prostate biopsy. The 4Kscore was significantly associated with the number of positive cores (p=0.039) and the millimeters of cancer seen (p=0.008), with higher 4Kscores relating to more extensive cancer present on biopsy. In the subpopulation of 49 men who underwent radical prostatectomy, the median 4Kscore was significantly higher among men who had an upgrade to Gleason 7 or higher [15% (8,25)] compared to men who did not experience an upgrade [9% {4,14)] (p=0.032) in their final pathology. CONCLUSIONS Among men with Gleason 6 prostate cancer on biopsy, we found the 4Kscore was associated with the prostate cancer being upgraded in the surgical specimen at radical prostatectomy. The 4Kscore test may facilitate the selection of men who can be observed versus those who should undergo immediate treatment. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1001 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanoj Punnen More articles by this author Stephen Zappala More articles by this author Dan Sjoberg More articles by this author Vinita Mathur More articles by this author Michael Reeve More articles by this author Dipen Parekh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP61-07 SERUM MICRORNA ANALYSIS: A MINIMALLY INVASIVE ASSAY CORRELATED WITH UPGRADING IN PATIENTS WITH LOW-RISK PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Pathologic upgrading from biopsy to prostatectomy occurs in approximately 30% of prostate cancer cases. PSA, a nonspecific protein, has previously been the primary serum marker for prostate cancer. Markers that more accurately assess risk of aggressiveprostate cancer at the timeof screening are critical for the future management of this disease. The aim of this study was to identify a panel of microRNA (miRNA) from serum that could differentiate patients with low-risk (Gleason 6) prostate cancer on TRUS biopsy specimenswho were either the same grade or upgraded at the time of prostatectomy. METHODS: Total RNA was isolated from serum of patients who had Gleason Sum (GS) 6 prostate cancer at the time of TRUS guided prostate biopsy. These patients were divided into groups with GS 6 that remained GS 6 (same grade) at prostatectomy and those who were upgraded to GS7 (upgrade) at the time of prostatectomy. For the discovery phase, sample pools from each group were profiled via miRNA PCR array (Exiqon). Validation of miRNA expression levels was performed on 29 same and 31 upgrade samples by qRT-PCR. RESULTS: Array analysis of 751miRNA identified34miRNAwith 2-fold differential expression between patients who had Gleason upgrading between biopsies and prostatectomy compared to patients who were same grade. Of these, 20 miRNA were down-regulated and 14 were up-regulated in theupgradedgroup.Additionally, 3miRNAwereexpressed in the upgrade groupwhich were not detected in the same grade group. 17 miRNA were further validated by qRT-PCR on individual samples. miR425-5pandmiR-146-5pwere found tobesignificantlydifferent between the same grade and upgraded groups. ROC curve of logistic regression analysis of theses two showed an area under the curve of 0.691. CONCLUSIONS: Serum samples demonstrated different miRNA expression levels between samples that were same grade or upgraded from Gleason 6 at prostatectomy. This minimally invasive assay could provide an adjunct to PSA and prostate biopsies to better counsel patients on management of low-risk prostate cancer and monitor patients on active surveillance.

Radiogenomics of prostate cancer: Association between qunatitative multiparametric MRI features and PTEN.

126 Background: Better methods are needed to assess prior to prostatectomy the risk of aggressive prostate cancer. Radiogenomics is a promising new paradigm that aims to gain molecular and genomic insights from clinical images. Loss of PTEN expression correlates with clinically aggressive disease and is associated with a 7-fold increase in the risk of prostate cancer death. Methods: From 38 patients who had undergone multi-parametric prostate MRI prior to prostatectomy, a pathologist and a radiologist simultaneously identified 45 peripheral-zone cancer regions of interest (ROIs). Histologic sections of the cancer foci underwent immunohistochemical analysis and were scored according to percent of tumor cells expressing PTEN as: negative (0-20%), mixed (20-80%), or positive (80-100%). From the MRI ROIs, the average and 10th percentile ADC values, T2-weighted signal-intensity histogram skewness, and quantitative perfusion parameters were calculated. Both dynamic perfusion two-compartment model and an empirical mathematical model (EMM) were used to fit the average contrast concentration curves within the ROIs as a function of time. Associations between the quantitative image features and PTEN expression were analyzed with Pearson's correlation coefficient (r). Results: The PTEN scores were: positive (n = 21, 47%), mixed (n = 12, 27%), and negative (n = 12, 27%). Two perfusion imaging contrast uptake parameters obtained from EMM correlated with PTEN scores (r = 0.25, p &lt; 0.1 and r = 0.43, p &lt; 0.01), and T2-weighted signal-intensity skewness also showed some correlation tendency (r = −0.25, p &lt; 0.1). No correlation was seen between mean ADC and 10th percentile ADC values and PTEN score. Conclusions: This preliminary study of radiogenomics of prostate cancer suggests that fast contrast uptake of cancer on DCE-MR imaging and a T2-weighted imaging feature are potentially associated with prostate cancer PTEN expression, which warrants further studies and validation.

Circulating leukocyte telomere length and risk of overall and aggressive prostate cancer.

Background:Recent large-scale prospective studies suggest that long telomeres are associated with an increase cancer risk, counter to conventional wisdom.Methods:To further clarify the association between leukocyte telomere length (LTL) and prostate cancer, and assess genetic variability in relation to both LTL and prostate cancer, we performed a nested case–control study (922 cases and 935 controls). The participants provided blood in 1993–1995 and were followed through August 2004 (prostate cancer incidence) or until 28 February 2013 (lethal or fatal prostate cancer). Relative LTL was measured by quantitative PCR and was calculated as the ratio of telomere repeat copy number to a single gene (36B4) copy number (T/S). Genotyping was performed using the TaqMan OpenArray SNP Genotyping Platform. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of all prostate cancer and subtypes defined by Gleason grade, stage and lethality (metastasis or death).Results:We observed a positive association between each s.d. increase in LTL and all (multivariable-adjusted OR 1.11, 95% CI: 1.01–1.22), low-grade (OR 1.13, 95% CI:1.01–1.27), and localised (OR 1.12, 95% CI:1.01–1.24) prostate cancer. Associations for other subtypes were similar, but did not reach statistical significance. In subgroup analyses, associations for high grade and advanced stage (OR=2.04, 95% CI 1.00–4.17; Pinteraction=0.06) or lethal disease (OR=2.37, 95% CI 1.19–4.72; Pinteraction=0.01) were stronger in men with a family history of the disease compared with those without. The minor allele of SNP, rs7726159, which has previously been shown to be positively associated with LTL, showed an inverse association with all prostate cancer risk after correction for multiple testing (P=0.0005).Conclusion:In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer. A stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.

Effect of individual omega-3 fatty acids on the risk of prostate cancer: a systematic review and dose-response meta-analysis of prospective cohort studies.

Epidemiological studies have suggested inconsistent associations between omega-3 polyunsaturated fatty acids (n-3 PUFAs) and prostate cancer (PCa) risk. We performed a dose-response meta-analysis of prospective observational studies investigating both dietary intake and circulating n-3 PUFAs and PCa risk. PubMed and EMBASE prior to February 2014 were searched, and 16 publications were eligible. Blood concentration of docosahexaenoic acid, but not alpha-linolenic acid or eicosapentaenoic acid, showed marginal positive association with PCa risk (relative risk for 1% increase in blood docosahexaenoic acid concentration: 1.02; 95% confidence interval, 1.00–1.05; I2 = 26%; P = 0.05 for linear trend), while dietary docosahexaenoic acid intake showed a non-linear positive association with PCa risk (P < 0.01). Dietary alpha-linolenic acid was inversely associated with PCa risk (relative risk for 0.5 g/day increase in alpha-linolenic acid intake: 0.99; 95% confidence interval, 0.98–1.00; I2 = 0%; P = 0.04 for linear trend), which was dominated by a single study. Subgroup analyses indicated that blood eicosapentaenoic acid concentration and blood docosahexaenoic acid concentration were positively associated with aggressive PCa risk and nonaggressive PCa risk, respectively. Among studies with nested case-control study designs, a 0.2% increase in blood docosapentaenoic acid concentration was associated with a 3% reduced risk of PCa (relative risk 0.97; 95% confidence interval, 0.94–1.00; I2 = 44%; P = 0.05 for linear trend). In conclusion, different individual n-3 PUFA exposures may exhibit different or even opposite associations with PCa risk, and more prospective studies, especially those examining dietary n-3 PUFAs and PCa risk stratified by severity of cancer, are needed to confirm the results.

Impact of obesity upon prostate cancer-associated mortality: A meta-analysis of 17 cohort studies

A number of epidemiological studies have suggested that obesity is associated, albeit inconsistently, with the incidence of prostate cancer (PCa). In order to provide a quantitative assessment of this association, the present study examined the correlation between obesity and the incidence and associated mortalities of PCa in an updated meta-analysis of cohort studies. The cohort studies were identified by searching the EMBASE and MEDLINE databases on January 1, 2014. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. In total, 17 studies, which included 3,569,926 individuals overall, were selected according to predefined inclusion criteria. Based upon the results of the random-effects models, obesity was not significantly correlated with the incidence of PCa (RR, 1.00; 95% CI, 0.95–1.06). However, further analysis revealed that obesity was significantly correlated with an increased risk of aggressive PCa (RR, 1.14; 95% CI, 1.04–1.25). Furthermore, an increased risk of PCa-associated mortality was significantly associated with obesity (RR, 1.24; 95% CI, 1.15–2.33), without any heterogeneity between the studies (I2=0.0%; P=0.847). The present study provides preliminary evidence to demonstrate that obesity is a significant risk factor for aggressive PCa and PCa-specific mortality. The low survival rates observed among obese males with PCa may be a likely explanation for this association.

Male pattern baldness in relation to prostate cancer risks: an analysis in the VITamins and lifestyle (VITAL) cohort study.

Male pattern baldness and prostate cancer may share common pathophysiological mechanisms in terms of advancing age, heritability, and endogenous hormones. Results from previous epidemiologic studies are inconsistent. Therefore, we investigated the association of prostate cancer risks with male pattern baldness at age 30 years, age 45 years, and baseline (median age = 60.5 years) in the VITamins And Lifestyle (VITAL) cohort study. We included 32,583 men who were aged 50-76 years and without prior cancer diagnosis (excluding non-melanoma skin cancer) at the start of follow-up. First primary incident prostate cancers were ascertained via linkage to the western Washington Surveillance, Epidemiology, and End Results (SEER) program. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regressions with adjustment for potential confounders. During follow-up (median = 9 years), 2,306 incident prostate cancers were diagnosed. Male pattern baldness at age 30 years, age 45 years, and baseline were not statistically significantly associated with overall or subtypes of prostate cancer. This study did not provide support for the hypothesis that male pattern baldness may be a marker for subsequent prostate cancer. Previous evidence indicates that a distinct class of frontal with vertex balding may be associated with increased risk of aggressive prostate cancer, but all such balding classes were captured as a single exposure category by the VITAL cohort questionnaire. Prostate 75:415-423, 2015. © 2014 Wiley Periodicals, Inc.

Commentary on "Region 2 of 8q24 is associated with the risk of aggressive prostate cancer in Caribbean men of African descent from Guadeloupe (French West Indies)".

Commentary on "Region 2 of 8q24 is associated with the risk of aggressive prostate cancer in Caribbean men of African descent from Guadeloupe (French West Indies)".

Sex steroid hormone metabolism in relation to risk of aggressive prostate cancer.

The combined action of androgens and estrogens-specifically their balance-may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer. In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI). Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st = 0.27; 95% CI, 0.12-0.59, Ptrend = 0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st = 2.44; 95% CI, 1.34-4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk. Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer. Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions.

Racial differences in adipose tissue distribution and risk of aggressive prostate cancer among men undergoing radiotherapy.

Although elevated body mass index (BMI) has been associated with increased risk of aggressive prostate cancer, the importance of adipose tissue distribution is not well understood. We examined associations between overall and visceral obesity and aggressive prostate cancer risk. Moreover, given racial differences in adipose tissue distribution, we examined whether race modified these associations. We conducted a cross-sectional analysis of 308 radiotherapy-treated patients with prostate cancer within the Durham VA from 2005 to 2011. Multivariable logistic regression examined the association between BMI categories and tertiles of waist circumference (WC), visceral fat area (VFA), and periprostatic adipose tissue area (PPAT) with high-grade prostate cancer risk (Gleason score ≥7 vs. ≤6). Models stratified by race examined whether these associations differed between black and nonblack men. Both elevated BMI (Ptrend = 0.054) and WC (Ptrend = 0.040) were associated with increased high-grade prostate cancer risk, with similar results between races, although the association with BMI was not statistically significant. In contrast, elevated VFA was associated with increased aggressive prostate cancer risk in black men (Ptrend = 0.002) but not nonblack men (Ptrend = 0.831), with a significant interaction between race and VFA (Pinteraction = 0.035). Though similar patterns were observed for PPAT, none was statistically significant. Among men undergoing radiotherapy for prostate cancer, visceral obesity is associated with increased aggressive prostate cancer risk, particularly among black men. If confirmed in future studies, these results suggest that adipose tissue distribution differences may contribute to prostate cancer racial disparity. These findings highlight the need to elucidate mechanisms contributing to racial differences in the association between visceral obesity and aggressive prostate cancer.

Abstract PL01-03: Vitamin D deficiency and prostate cancer in men with African ancestry

Abstract African-American men are disproportionally affected by prostate cancer in that African-American men are not only at increased risk of prostate cancer compared to American men of European descent, but also are at the highest risk of aggressive prostate cancer and death from prostate cancer. As well vitamin D3 deficiency is rampant in the African-American population. There is a biological component to this deficiency because sun-induced vitamin D3 synthesis in the skin is significantly reduced in melanin-rich pigmented skin. Consequently, about two thirds of African-American men are vitamin D3 deficient compared to about 20% of men of European descent. It is important to maintain a healthy vitamin D3 status because vitamin D3 deficiency increases the risk of prostate cancer mortality. Our group has examined vitamin D3 concentrations, metabolism and mediators in prostate tissue and cells of a racially diverse group of patients to discern differences in African-American men. Citation Format: Larisa Nonn. Vitamin D deficiency and prostate cancer in men with African ancestry. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PL01-03. doi:10.1158/1538-7755.DISP13-PL01-03