A. Karim Kader

Cumulative Association of Five Genetic Variants with Prostate Cancer

BACKGROUND Single-nucleotide polymorphisms (SNPs) in five chromosomal regions--three at 8q24 and one each at 17q12 and 17q24.3--have been associated with prostate cancer. Each SNP has only a moderate association, but when SNPs are combined, the association may be stronger. METHODS We evaluated 16 SNPs from five chromosomal regions in a Swedish population (2893 subjects with prostate cancer and 1781 control subjects) and assessed the individual and combined association of the SNPs with prostate cancer. RESULTS Multiple SNPs in each of the five regions were associated with prostate cancer in single SNP analysis. When the most significant SNP from each of the five regions was selected and included in a multivariate analysis, each SNP remained significant after adjustment for other SNPs and family history. Together, the five SNPs and family history were estimated to account for 46% of the cases of prostate cancer in the Swedish men we studied. The five SNPs plus family history had a cumulative association with prostate cancer (P for trend, 3.93x10(-28)). In men who had any five or more of these factors associated with prostate cancer, the odds ratio for prostate cancer was 9.46 (P=1.29x10(-8)), as compared with men without any of the factors. The cumulative effect of these variants and family history was independent of serum levels of prostate-specific antigen at diagnosis. CONCLUSIONS SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer.

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer

Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 × 10−8 under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non–organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.

Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.

More than a dozen single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk from genome‐wide association studies (GWAS). Their association with PCa aggressiveness and clinicopathologic variables is inconclusive.

Estimation of absolute risk for prostate cancer using genetic markers and family history

Multiple DNA sequence variants in the form of single‐nucleotide polymorphisms (SNPs) have been found to be reproducibly associated with prostate cancer (PCa) risk.

Prostate cancer risk-associated variants reported from genome-wide association studies: meta-analysis and their contribution to genetic variation

Genome‐wide association studies (GWAS) have led to the discovery of multiple single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk. These SNPs may potentially be used for risk prediction. To date, there is not a stable estimate of their effect on PCa risk and their contribution to the genetic variation both of which are important for future risk prediction.

Matrix Metalloproteinase Polymorphisms and Bladder Cancer Risk

Matrix metalloproteinases (MMP) contribute to tumor microenvironment and are associated with bladder cancer. A study examining the association between MMP polymorphisms and bladder cancer risk has never been published. We analyzed the association of 11 single nucleotide polymorphisms (SNPs) and one microsatellite polymorphism in MMP genes MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 with bladder cancer risk in 560 Caucasian patients and 560 controls matched on age, gender, and ethnicity. Individual, combination, haplotype, and diplotype analyses were done. No associations between individual MMP polymorphisms and overall bladder cancer risk were seen. The MMP-9 microsatellite > or =24 CA repeat allele and the MMP-12-82 GG polymorphisms were associated with invasive bladder cancer risk [odds ratio (OR), 2.60; 95% confidence interval (95% CI), 1.07-6.26; and OR, 4.59; 95% CI, 1.21-17.32, respectively]. Smoke-stratified analyses revealed several associations between MMP polymorphisms, alone and in combination, with bladder cancer risk, particularly in light smokers. Linkage disequilibrium was seen in all of the MMP-1, MMP-3, MMP-8, and MMP-12 SNPs and in four of five MMP-9 polymorphisms tested. Several MMP-9 haplotype and diplotypes were associated with overall and invasive bladder cancer risk. Our study suggests that genetic variations in the MMP family are associated with bladder cancer risk. Heavy carcinogen exposure may overwhelm some of the genetic effects of MMP polymorphisms. Our study confirms the importance of taking a multigenic pathway-based approach to risk assessment.

Robot-assisted laparoscopic vs open radical cystectomy: comparison of complications and perioperative oncological outcomes in 200 patients

To compare perioperative morbidity and oncological outcomes of robot‐assisted laparoscopic radical cystectomy (RARC) to open RC (ORC) at a single institution.

Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial.

BACKGROUND Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk. OBJECTIVE To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa. DESIGN, SETTING, AND PARTICIPANTS Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 yr and 4 yr. Predictive performance of baseline clinical parameters and/or a genetic score based on 33 established PCa risk-associated SNPs was evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Area under the receiver operating characteristic curves (AUC) were used to compare different models with different predictors. Net reclassification improvement (NRI) and decision curve analysis (DCA) were used to assess changes in risk prediction by adding genetic markers. RESULTS AND LIMITATIONS Among 1654 men, genetic score was a significant predictor of positive biopsy, even after adjusting for known clinical variables and family history (p = 3.41 × 10(-8)). The AUC for the genetic score exceeded that of any other PCa predictor at 0.59. Adding the genetic score to the best clinical model improved the AUC from 0.62 to 0.66 (p<0.001), reclassified PCa risk in 33% of men (NRI: 0.10; p=0.002), resulted in higher net benefit from DCA, and decreased the number of biopsies needed to detect the same number of PCa instances. The benefit of adding the genetic score was greatest among men at intermediate risk (25th percentile to 75th percentile). Similar results were found for high-grade (Gleason score ≥ 7) PCa. A major limitation of this study was its focus on white patients only. CONCLUSIONS Adding genetic markers to current clinical parameters may improve PCa risk prediction. The improvement is modest but may be helpful for better determining the need for repeat prostate biopsy. The clinical impact of these results requires further study.

Robot Assisted Laparoscopic Pelvic Lymphadenectomy at the Time of Radical Cystectomy Rivals That of Open Surgery: Single Institution Report

OBJECTIVE The purpose of this study was to analyze the pelvic lymph node dissection (PLND) and margin status using a standard technique in the first 35 patients undergoing robot-assisted radical cystectomy (RARC) at our institution while establishing a robotics program, and then to compare the results to the past 35 open radical cystectomy (ORC) performed at our institution. MATERIALS AND METHODS After obtaining institutional review board approval, we reviewed the clinical and pathologic data from 70 consecutive patients with clinically localized bladder cancer who underwent radical cystectomy with PLND from April 2007 to June 2009. Thirty-five operations were performed open and 35 used the da Vinci robotic system. The PLND was performed in all patients using the same template. RESULTS There was no significant difference between the ORC and RARC group in regards to patient characteristics, tumor stage (43% ORC and 40% RARC having pT3/pT4 disease), and node status (29% N+ in each group). The median total lymph node yield was similar, with 15 (interquartile range [IQR] 11, 22) in the ORC group and 16 (IQR 11, 24) in the RARC group (P = 0.5). One patient who underwent RARC had a positive margin compared with 3 patients in the ORC group. CONCLUSIONS The initial 35 RARC with PLND performed at our institution compared with the last 35 ORC resulted in equivalent lymph node yield and similar rates of positive margins. RARC with PLND is feasible, safe, and effective when performed at a high-volume center by an experienced team.

Preoperative Neutrophil/Lymphocyte Ratio Predicts Overall Survival and Extravesical Disease in Patients Undergoing Radical Cystectomy

PURPOSE To evaluate if hematologic parameters and inflammatory markers could predict extravesical tumor and overall survival after radical cystectomy for patients with recurrent high grade T1 or muscle-invasive bladder cancer. PATIENTS AND METHODS A total of 68 consecutive cases of radical cystectomy performed with curative intent at our institution between April 2005 and October 2011 with preoperative hematologic parameters are included in this analysis. We evaluated preoperative characteristics with univariable and multivariate Cox proportional hazard ratios to assist in risk stratification for overall survival. Relative risk (RR) ratios and 95% confidence intervals (CI) were created. We also identified factors associated with extravesical tumor extension with logistic regression analysis. RESULTS Median overall survival in the total cohort was 25 months (95% CI 13-61). In multivariate analysis, neutrophil/lymphocyte ratio <2.5 (RR 2.49; 95% CI 1.14-6.09), hypoalbuminemia (RR 4.96; 95% CI 2.18-11.67), pT3/4 (RR 7.97, 95% CI 3.16-24.83), and lymph node positive disease (RR 2.62, 95% CI 1.26-5.46) predicted overall survival. These were statistically significant for cancer-specific survival as well. Both elevated neutrophil/lymphocyte ratio (RR 3.18, 95% CI 1.09-9.79) and hypoalbuminemia (RR 3.72, 95% CI 1.12-15.00) were associated with risk for extravesical disease. CONCLUSIONS Serum neutrophil/lymphocyte ratio and hypoalbuminemia predict overall and cancer-specific survival in patients undergoing radical cystectomy for muscle-invasive bladder cancer. These parameters also predict risk for extravesical disease. These could be combined with other established preoperative parameters to improve risk stratification and preoperative counseling.