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D'Antonio K.B.,The Brady Urological Institute | Toubaji A.,Johns Hopkins University | Albadine R.,Johns Hopkins University | Platz E.A.,The Brady Urological Institute | And 4 more authors.
Journal of Urology | Year: 2010

Purpose: The cancer cell microenvironment includes complex interactions between the cell and the extracellular matrix. Expression of the CCN family of extracellular matrix associated proteins is often modified in disease states. Depending on cancer type these changes are linked with enhanced or inhibited tumor growth. We characterized Cyr61 in prostate cancer. Cyr61 is an integrin binding matricellular protein with altered expression in many cancer types. Materials and Methods: Cyr61 expression in prostate cancer, benign prostatic hyperplasia and normal tissues was evaluated by microarray analysis, quantitative real-time polymerase chain reaction and tissue microarray. Immunoblots were analyzed to assess endogenous protein expression in prostate cancer cell lines. Results: On genomic analysis Cyr61 up-regulation was observed in prostate cancer tissue and in normal prostate tissue adjacent to tumor vs that in prostate donor tissue. In 174 matched tumors and normal prostate tissues adjacent to tumor tissue microarray revealed significantly up-regulated Cyr61 protein expression in cancer tissue vs normal prostate tissue adjacent to tumor. Also, increased Cyr61 expression correlated with Gleason sum 8 or greater cancer. Staining in high grade prostatic intraepithelial neoplasia was moderately up-regulated vs that in normal prostate tissue adjacent to tumor but generally less intense than in carcinoma tissue. Conclusions: In addition to the correlation with more advanced disease, the strong association between Cyr61 expression and prostate cancer supports the potential usefulness of Cyr61 as a novel biomarker for prostate cancer. This warrants further analysis to determine the mechanisms by which Cyr61 may contribute to prostate cancer development and progression. © 2010 American Urological Association Education and Research, Inc. Source

Schumacher F.R.,University of Southern California | Berndt S.I.,U.S. National Cancer Institute | Siddiq A.,Imperial College London | Jacobs K.B.,U.S. National Cancer Institute | And 68 more authors.
Human Molecular Genetics | Year: 2011

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 × 10 -8). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 × 10 -9). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P 5 0.72 and P 5 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes. © The Author 2011. Published by Oxford University Press. All rights reserved. Source

Elliott K.S.,University of Oxford | Zeggini E.,University of Oxford | Zeggini E.,Wellcome Trust Sanger Institute | Mccarthy M.I.,University of Oxford | And 37 more authors.
PLoS ONE | Year: 2010

Background: Genome-wide association studies have found type 2 diabetes-associated variants in the HNF1B gene to exhibit reciprocal associations with prostate cancer risk. We aimed to identify whether these variants may have an effect on cancer risk in general versus a specific effect on prostate cancer only. Methodology/Principal Findings: In a collaborative analysis, we collected data from GWAS of cancer phenotypes for the frequently reported variants of HNF1B, rs4430796 and rs7501939, which are in linkage disequilibrium (r2 = 0.76, HapMap CEU). Overall, the analysis included 16 datasets on rs4430796 with 19,640 cancer cases and 21,929 controls; and 21 datasets on rs7501939 with 26,923 cases and 49,085 controls. Malignancies other than prostate cancer included colorectal, breast, lung and pancreatic cancers, and melanoma. Meta-analysis showed large between-dataset heterogeneity that was driven by different effects in prostate cancer and other cancers. The per-T2D-risk-allele odds ratios (95% confidence intervals) for rs4430796 were 0.79 (0.76, 0.83)] per G allele for prostate cancer (p<10-15 for both); and 1.03 (0.99, 1.07) for all other cancers. Similarly for rs7501939 the per-T2D-risk-allele odds ratios (95% confidence intervals) were 0.80 (0.77, 0.83) per T allele for prostate cancer (p<10-15 for both); and 1.00 (0.97, 1.04) for all other cancers. No malignancy other than prostate cancer had a nominally statistically significant association. Conclusions/Significance: The examined HNF1B variants have a highly specific effect on prostate cancer risk with no apparent association with any of the other studied cancer types. © 2010 Elliott et al. Source

Makarov D.V.,Yale University | Loeb S.,The Brady Urological Institute | Landman A.B.,Yale University | Nielsen M.E.,University of North Carolina at Chapel Hill | And 4 more authors.
Journal of Urology | Year: 2010

Purpose: Surgical treatment for prostate cancer represents a large national health care expenditure. We determined whether state level variation in the cost of radical prostatectomy exists and whether we could explain this variation by adjusting for covariates associated with cost. Materials and Methods: Using the 2004 Healthcare Cost and Utilization Project National Inpatient Sample of 7,978,041 patients we identified 9,917 who were 40 years old or older with a diagnosis of prostate cancer who underwent radical prostatectomy without cystectomy. We used linear regression to examine state level regional variation in radical prostatectomy costs, controlling for the local area wage index, patient demographics, case mix and hospital characteristics. Results: The mean ± SD unadjusted cost was $9,112 ± $4,434 (range $2,001 to $49,922). The unadjusted mean cost ranged from $12,490 in California to $4,650 in Utah, each significantly different from the mean of $8,903 in the median state, Washington (p <0.0001). After adjusting for all potential confounders total cost was highest in Colorado and lowest in New Jersey, which were significantly different from the median, Washington ($10,750 and $5,899, respectively, vs $8,641, p <0.0001). The model explained 85.9% of the variance with regional variation accounting for the greatest incremental proportion of variance (35.1%) and case mix variables accounting for an incremental 32.3%. Conclusions: The total cost of radical prostatectomy varies significantly across states. Controlling for known total cost determinants did not completely explain these differences but altered ordinal cost relationships among states. Cost variation suggests inefficiencies in the health care market. Additional studies are needed to determine whether these variations in total cost translate into differences in quality or outcome and how they may be translated into useful policy measures. © 2010 American Urological Association Education and Research, Inc. Source

Yu J.B.,Yale University | Makarov D.V.,Yale University | Sharma R.,Yale University | Peschel R.E.,Yale University | And 2 more authors.
Journal of Urology | Year: 2010

Purpose: The Partin tables are a nomogram that is widely used to discriminate prostate cancer pathological stages, given common preoperative clinical characteristics. The nomogram is based on patients undergoing radical prostatectomy at The Johns Hopkins Medical Institutions. We validated the Partin tables in a large, population based sample. Materials and Methods: The National Cancer Institute Surveillance, Epidemiology and End Results database was used to identify patients treated from 2004 to 2005 who underwent radical prostatectomy. The 2007 Partin tables were used to estimate the prevalence of positive lymph nodes, seminal vesicle invasion, extraprostatic extension and organ confined disease in men with prostate cancer in the database using clinical stage, preoperative prostate specific antigen and Gleason score. The discriminative ability of the tables was explored by constructing ROC curves. Results: We identified 11,185 men who underwent radical prostatectomy for prostate cancer in 2004 to 2005. The Partin tables discriminated well between patient groups at risk for positive lymph nodes and seminal vesicle invasion (AUC 0.77 and 0.74, respectively). The discrimination of extraprostatic extension and organ confined disease was more limited (AUC 0.62 and 0.68, respectively). The AUC for positive lymph nodes was 0.78 in white men, 0.73 in black men and 0.83 in Asian/Pacific Islander men (p = 0.17). The AUC for positive lymph nodes in men 61 years old or younger was 0.80 vs 0.74 in men older than 61 years (p = 0.03). Conclusions: The Partin tables showed excellent discrimination for seminal vesicle invasion and positive lymph nodes. Discrimination of extraprostatic extension and organ confined disease was more limited. The Partin tables performed best in young men. © 2010 American Urological Association. Source

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