Saundra Motley

Oxidative stress measured by urine F2-isoprostane level is associated with prostate cancer

PURPOSE Oxidative stress is implicated in prostate cancer by several lines of evidence. We studied the relationship between the level of F2-isoprostanes, a validated biomarker of oxidative stress, and prostate cancer and high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS This case-control analysis within the Nashville Mens Health Study included men recruited at prostate biopsy. Body morphometrics, health history and urine were collected from more than 2,000 men before biopsy. F2-isoprostanes were measured by gas chromatography/mass spectrometry within an age matched sample of Nashville Mens Health Study participants that included 140 patients with high grade prostatic intraepithelial neoplasia, 160 biopsy negative controls and 200 prostate cancer cases. Multivariable linear and logistic regression was used to determine the associations between F2-isoprostane level, and high grade prostatic intraepithelial neoplasia and prostate cancer. RESULTS Mean patient age was 66.9 years (SD 7.2) and 10.1% were nonwhite. Adjusted geometric mean F2-isoprostane levels were higher in patients with prostate cancer (1.82, 95% CI 1.66-2.00) or high grade prostatic intraepithelial neoplasia (1.82, 95% CI 1.68-1.96) than in controls (1.63, 95% CI 1.49-1.78, p <0.001), but were similar across Gleason scores (p = 0.511). The adjusted odds of high grade prostatic intraepithelial neoplasia and prostate cancer increased with increasing F2-isoprostane quartile (p-trend = 0.015 and 0.047, respectively) and the highest F2-isoprostane quartile was associated with significantly increased odds of prostate cancer (OR 2.44, 95% CI 1.17-5.09, p = 0.017). CONCLUSIONS Pre-diagnosis urine F2-isoprostane level is increased in men with high grade prostatic intraepithelial neoplasia or prostate cancer, suggesting urinary F2-isoprostane provides a biomarker for the role for oxidative stress in prostate carcinogenesis. F2-isoprostanes may also serve to estimate the efficacy of interventions targeting oxidative stress mechanisms in prostate cancer prevention or treatment.

Obesity, body composition, and prostate cancer

BackgroundEstablished risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer.MethodsThe study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression.ResultsBody size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (ORBMI = 1.039 (1.000, 1.081), ORWC = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (ORBMI = 0.998 (0.946, 1.052), ORWC = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (ORFFM = 1.030 (1.008, 1.052)) and Gleason 8-10 (ORFFM = 1.044 (1.014, 1.074)) after controlling for FM.ConclusionsOur results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age.

Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer

Background Ionized calcium (Ca) and magnesium (Mg) compete as essential messengers to regulate cell proliferation and inflammation. We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk. Study Design In this biomarker sub-study of the Nashville Mens Health Study (NMHS), we included 494 NMHS participants, consisting of 98 high-grade (Gleason≥7) and 100 low-grade cancer cases, 133 prostate intraepithelial neoplasia (PIN) cases, and 163 controls without cancer or PIN at biopsy. Linear and logistic regression were used to determine associations between blood Ca, Mg, and the Ca/Mg ratio across controls and case groups while adjusting for potential confounding factors. Results Serum Mg levels were significantly lower, while the Ca/Mg ratio was significantly higher, among high-grade cases vs. controls (p = 0.04, p = 0.01, respectively). Elevated Mg was significantly associated with a lower risk of high-grade prostate cancer (OR = 0.26 (0.09, 0.85)). An elevated Ca/Mg ratio was also associated with an increased risk of high-grade prostate cancer (OR = 2.81 (1.24, 6.36) adjusted for serum Ca and Mg). In contrast, blood Ca levels were not significantly associated with prostate cancer or PIN.Mg, Ca, or Ca/Mg levels were not associated with low-grade cancer, PIN, PSA levels, prostate volume, or BPH treatment. Conclusion Low blood Mg levels and a high Ca/Mg ratio were significantly associated with high-grade prostate cancer. These findings suggest Mg affects prostate cancer risk perhaps through interacting with Ca.

Association of Nonsteroidal Anti-Inflammatory Drugs, Prostate Specific Antigen and Prostate Volume

PURPOSE Nonsteroidal anti-inflammatory drugs such as aspirin prevent cardiovascular disease and several prior studies suggest that nonsteroidal anti-inflammatory drugs also decrease prostate inflammation and prostate cancer risk. We investigated the association between nonsteroidal anti-inflammatory drug use, prostate specific antigen and prostate volume, hypothesizing that there would be lower prostate specific antigen and prostate volume with nonsteroidal anti-inflammatory drug use. MATERIALS AND METHODS The Nashville Mens Health Study uses a multicenter, rapid recruitment protocol to collect clinical, biological, behavioral and body measurement data on 1,277 men older than 40 years who are scheduled for diagnostic prostate biopsy. Nonsteroidal anti-inflammatory drug use was ascertained by survey and clinical interview. Medical charts were reviewed to ascertain current prostate specific antigen, prostate volume and clinical diagnoses following biopsy. RESULTS Approximately 46% of patients reported receiving nonsteroidal anti-inflammatory drugs, primarily aspirin (37%). After adjusting for age, race and other factors prostate volume was similar between aspirin users and nonusers (47.6 vs 46.0 ml, p = 0.16). In contrast, prostate specific antigen was significantly lower in aspirin users (7.3 vs 8.0 ng/ml, p = 0.01). The association between prostate specific antigen and aspirin was significant in men with latent prostate cancer (6.1 vs 7.3 ng/ml, p <0.01), marginal in patients with high grade prostatic intraepithelial neoplasia (5.0 vs 5.9 ng/ml, p = 0.09) and nonsignificant in those with a negative biopsy (5.6 vs 5.7 ng/ml, p = 0.64). The strongest prostate specific antigen-aspirin association was in men with cancer and a prostate volume of 60 ml or more (7.3 vs 12.7 ng/ml, p <0.01). CONCLUSIONS Prostate specific antigen was significantly lower in aspirin users with latent cancer. Prostate volume was not associated with nonsteroidal anti-inflammatory drug use. Results suggest that aspirin may affect prostate cancer detection, suggesting a potential detection bias to address in future studies of nonsteroidal anti-inflammatory drugs and prostate cancer prevention.

Association between physical activity, lower urinary tract symptoms (LUTS) and prostate volume

Greater leisure‐time physical activity (PA) levels or a lower body mass index have previously been associated with a lower risk of benign prostatic hyperplasia or less severe lower urinary tract symptoms (LUTS). However, separating the effects of PA from obesity can be difficult, and the types of PA and the mechanisms underlying any association with LUTS among older men are unclear. The present analysis used multiple validated instruments to measure PA domains across workplace, leisure time, and home domains, and finds that PAs ranging from sports to light housework are associated with lower LUTS severity. The benefits of PA were seen with irritative symptoms, and also among obese men. Furthermore, this analysis begins the investigation of mechanism by finding that the relationship between PA and LUTS is not mediated by prostate enlargement.

Association between biomarkers of obesity and risk of high-grade prostatic intraepithelial neoplasia and prostate cancer – Evidence of effect modification by prostate size

Prostate enlargement is common with aging and obesity. We investigated the association between obesity and prostate cancer controlling for differential detection related to prostate enlargement. In an analysis of 500 men, we found body mass index, waist-hip ratio, and blood leptin levels were significantly associated with high-grade PC, but only among men without prostate enlargement. Leptin was also significantly associated with high-grade prostatic intraepithelial neoplasia (HGPIN) in the absence of prostate enlargement. Our results suggest obesity advances prostate carcinogenesis, and that detection biases at prostate biopsy may explain past inconsistencies in the association between obesity and PC.

Prostate volume modifies the association between obesity and prostate cancer or high-grade prostatic intraepithelial neoplasia

The relationship between obesity and prostate cancer remains unclear. We investigated the effect of prostate volume on the obesity and prostate cancer association. With a multi-centered, rapid-recruitment protocol, weight and body size measurements were collected prior to diagnosis, and medical charts were reviewed for pathology results (n = 420 controls, 119 high-grade prostatic intraepithelial neoplasia (PIN) cases, and 286 cancer cases (41% Gleason > 6). In multivariable logistic regression models adjusting for age, PSA levels and history, DRE results, and number of cores at biopsy, the association between BMI and cancer was restricted to men with a smaller prostate volume (volume < 40 cm3: ORBMI ≥ 30 = 2.17 (1.09, 4.32), ptrend = 0.02; volume ≥ 40 cm3: ORBMI ≥ 30 = 0.77 (0.34, 1.77), ptrend = 0.17; pinteraction = 0.03). Similarly, the WHR and PIN association was significantly modified by prostate volume (volume < 40 cm3: OR(WHR: Tertile 3 vs. T1) = 3.76 (1.54, 9.21) (ptrend < 0.01); volume ≥ 40 m3: OR(WHR: T3 vs. T1) = 0.63 (0.32, 1.23) (ptrend = 0.17); pinteraction < 0.01). In conclusion, prostate volume acts as a modifier, and BMI and WHR are significantly associated with prostate cancer or PIN, respectively, in the absence of biopsy sampling error derived from obesity-related prostate enlargement.

Genetic Determinants of Metabolism and Benign Prostate Enlargement: Associations with Prostate Volume

Prostate enlargement leading to clinical benign prostatic hyperplasia (BPH) is associated with metabolic dysregulation and obesity. The genetic basis of this association is unclear. Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) previously associated with metabolic disorders are also associated with prostate volume (PV). Participants included 876 men referred for prostate biopsy and found to be prostate cancer free. PV was measured by transrectal ultrasound. Samples were genotyped using the Illumina Cardio-MetaboChip platform. Multivariable adjusted linear regression models were used to evaluate SNPs (additive coding) in relation to natural-log transformed (log) PV. We compared SNP-PV results from biopsy-negative men to 442 men with low-grade prostate cancer with similar levels of obesity and PV. Beta-coefficients from the discovery and replication samples were then aggregated with fixed effects inverse variance weighted meta-analysis. SNP rs11736129 (near the pseudo-gene LOC100131429) was significantly associated with log-PV (beta: 0.16, p-value 1.16x10-8) after adjusting for multiple testing. Other noteworthy SNPs that were nominally associated (p-value < 1x10-4) with log-PV included rs9583484 (intronic SNP in COL4A2), rs10146527 (intronic SNP in NRXN3), rs9909466 (SNP near RPL32P31), and rs2241606 (synonymous SNP in SLC12A7). We found several SNPs in metabolic loci associated with PV. Further studies are needed to confirm our results and elucidate the mechanism between these genetic loci, PV, and clinical BPH.

Pleiotropy between Genetic Markers of Obesity and Risk of Prostate Cancer

Background: To address inconsistent findings of obesity and prostate cancer risk, we analyzed the association between prostate cancer and genetic markers of obesity and metabolism. Methods: Analyses included 176,520 single-nucleotide polymorphisms (SNP) associated with 23 metabolic traits. We examined the association between SNPs and prostate cancer in 871 cases and 906 controls, including 427 high-grade cases with Gleason ≥ 7. Genetic risk scores (GRS) for body mass index (BMI) and waist-to-hip ratio (WHR) were also created by summing alleles associated with increasing BMI or WHR. Results: Prostate cancer was associated with five loci, including cyclin M2, with P values less than 1 × 10−4. In addition, the WHR GRS was associated with high-grade prostate cancer versus controls [OR, 1.05; 95% confidence interval (CI), 1.00–1.11; P = 0.048] and high-grade prostate cancer versus low-grade prostate cancer (OR, 1.07; 95% CI, 1.01–1.13; P = 0.03). None of these findings exceeds the threshold for significance after correction for multiple testing. Conclusions: Variants in genes known to be associated with metabolism and obesity may be associated with prostate cancer. We show evidence for pleiotropy between WHR GRS and prostate cancer grade. This finding is consistent with the function of several WHR genes and previously described relationships with cancer traits. Impact: Limitations in standard obesity measures suggest alternative characterizations of obesity may be needed to understand the role of metabolic dysregulation in prostate cancer. The underlying genetics of WHR or other Metabochip SNPs, while not statistically significant beyond multiple testing thresholds within our sample size, support the metabolic hypothesis of prostate carcinogenesis and warrant further investigation in independent samples. Cancer Epidemiol Biomarkers Prev; 22(9); 1538–46. ©2013 AACR.

Statin use linked with a decrease in the conversion from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer

The roles of obesity, metabolic dysregulation and systemic inflammation to advance prostate carcinogenesis are unclear. This study investigates metabolic and inflammatory factors in the transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer (PC). We prospectively followed 160 men diagnosed with HGPIN at biopsy and therefore at high-risk and clinically monitored for PC. Analyses investigated body mass index (BMI), waist circumference, waist-hip ratio (WHR), height, fat mass, lean mass percent body fat, NSAIDs, statins, metformin, diabetes, hypertension, hypercholesterolemia representing metabolic dysregulation on the risk of a PC diagnosis during follow-up. Systemic inflammation was estimated through measurement of 13 plasma cytokine levels. Statin use was significantly linked with overall PC at follow-up [odds ratio (OR) = 0.45, (0.23, 0.91), P = 0.03], with a somewhat stronger link with high-grade [OR = 0.39, (0.15, 1.04), P = 0.06] PC compared with low-grade PC [OR = 0.50, (0.23, 1.12), P = 0.09]. Non-statin cholesterol-lowering medications, BMI, WHR, diabetes, hypertension and percent body fat were not significantly associated with PC. Although blood IL-12p70, IL-2 and IL-1β levels were significantly lower among statin users, inflammatory markers were not significantly linked with PC and did not explain the observed relationship between statins and lower PC risk. In summary, this prospective study of HGPIN patients at high risk for PC finds that statin use was significantly associated with reduced risk of PC detection at follow-up. Systemic markers of inflammation did not mediate this association, suggesting that statins affect PC progression through alternative pathways.