Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. SIGNIFICANCE: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK-GATA3-ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

Clinical significance of urine prostatic exosomal protein in the diagnosis of prostate cancer.

PSA may be elevated in non-malignant conditions such as prostatitis and leads to unnecessary prostate needle biopsy. Urine prostatic exosomal protein (PSEP) has been proved to be a promising biomarker of prostatic inflammation. The aim of this study is to determine the relationships between PSEP and the diagnosis of prostate cancer (PCa), and their association with histologic prostatic inflammation. Prostate needle biopsies from 674 patients were evaluated for the presence of histological inflammation and PCa. The urine PSEP levels were measured using an enzyme-linked immunosorbent assay kit. 286 cases were diagnosed as PCa and prostatic inflammation was observed in 33.7% of the biopsies. The presence of histological inflammation was significantly associated with a lower PCa risk (P < 0.001). The urine PSEP levels was significantly lower in PCa patients compared to the controls (P = 0.003). When subanalyzed by PSA levels, the difference was more evident in cases with PSA 4-10 ng/ml (P = 0.039). The urine PSEP levels was correlated with histological inflammation on prostate needle biopsy (P = 0.018, r = 0.12). Urine PSEP examination may be helpful to eliminate false positive PSA levels due to prostatic inflammation and reduce unnecessary prostate needle biopsy in cases with PSA grey zone.

Preoperative prostate health index predicts poor pathologic outcomes of radical prostatectomy in patients with biopsy-detected low-risk patients prostate cancer: results from a Chinese prospective cohort.

OBJECTIVE: To determine the performance of the prostate health index (PHI) in predicting pathologic outcomes of radical prostatectomy (RP) in Chinese patients with low-risk prostate cancer (PCa). METHODS: Of all consecutive patients who underwent RP in one tertiary center from September 2013 to January 2017, we prospectively examined the data of 140 patients with low-risk PCa based on the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria. All patients were eligible for active surveillance, but underwent RP. Clinical and pathological data were collected. Logistic regression was used to evaluate the associations between the PHI and outcome of RP. The area under the receiver operating curve (AUC) was used to evaluate the accuracy of different models. Decision curve analysis was used to evaluate the potential clinical usefulness of making model-based decisions. RESULTS: Only 44 (31.4%) patients were finally confirmed to have organ-confined Gleason ≤6 PCa. A low PHI was significantly predictive of organ-confined Gleason ≤6 PCa (p = 0.001), while tPSA and f/tPSA were not associated with final pathology. In the multivariate analyses, addition of the PHI significantly increased the predictive accuracy (AUC = 0.767, 95% Cl 0.685-0.849, p < 0.001). CONCLUSION: The PRIAS criteria for active surveillance may not suitable for Chinese patients with PCa. Addition of the PHI to the PRIAS models improved the prognostic performance. If confirmed in future larger and multicenter studies, PHI may help us to identify patients eligible for AS in China.

Smoking increased the risk of prostate cancer with grade group ≥ 4 and intraductal carcinoma in a prospective biopsy cohort.

OBJECTIVE: To investigate the association between smoking and different prostate cancer (PCa) pathological subtypes incidence in Chinese men. PATIENTS AND METHODS: We prospectively included 1795 patients who underwent prostate biopsies in one tertiary center between March 2013 and April 2016. Clinical data and biopsy outcomes were collected. Logistic regression was used to evaluate the association between cigarette smoking and PCa incidence. RESULTS: A total of 737 men, 480 men and 58 men were diagnosed with PCa, high-grade PCa (HGPCa, grade group ≥ 4 as accepted by the 2014 ISUP) and intraductal carcinoma of the prostate (IDC-P), respectively. Current smokers had a significantly higher risk of HGPCa than never smokers (OR = 1.89, 95%CI: 1.44-2.48). No such association was observed for low-grade disease and cigarette smoking (OR = 0.84, 95%CI: 0.61-1.16). In a sub-analysis, men who had smoked longer than 30 years had a higher risk of HGPCa, compared with men who had smoked fewer than 30 years (OR = 1.50, 95%CI: 1.09-2.06). Current smokers were more likely to develop IDC-P than never smokers (OR = 2.29, 95%CI: 1.14-4.59). CONCLUSION: Among men in this Chinese biopsy cohort, current smoking was associated with highly malignant PCa incidence, such as HGPCa and IDC-P. The duration of smoking may be associated with HGPCa.

Waist-hip Ratio (WHR), a Better Predictor for Prostate Cancer than Body Mass Index (BMI): Results from a Chinese Hospital-based Biopsy Cohort.

To investigate whether waist-hip ratio (WHR) is a better predictor of prostate cancer (PCa) incidence than body mass index (BMI) in Chinese men. Of consecutive patients who underwent prostate biopsies in one tertiary center between 2013 and 2015, we examined data on 1018 with PSA ≤20 ng/ml. Clinical data and biopsy outcomes were collected. Logistic regression was used to evaluate the associations between BMI, WHR and PCa incidence. Area under the ROC (AUC) was used to evaluate the accuracy of different prognostic models. A total of 255 men and 103 men were diagnosed with PCa and high grade PCa (HGPCa, Gleason score ≥8). WHR was an independent risk factor for both PCa (OR = 1.07 95%Cl 1.03-1.11) and HGPCa (OR = 1.14 95%Cl 1.09-1.19) detection, while BMI had no relationship with either PCa or HGPCa detection. Adding WHR to a multivariable model increased the AUC for detecting HGPCa from 0.66 (95%Cl 0.60-0.72) to 0.71 (95%Cl 0.65-0.76). In this Chinese cohort, WHR was significantly predictive of PCa and HGPCa. Adding WHR to a multivariable model increased the diagnostic accuracy for detecting HGPCa. If confirmed, including WHR measurement may improve PCa and HGPCa detection.

Effect of body mass index on the performance characteristics of PSA-related markers to detect prostate cancer.

To examine whether the predictive performance of prostate-specific antigen (PSA) and PSA-related markers for prostate cancer (PCa) is modified by body mass index (BMI). Patients with a PSA 2-10 ng/mL who underwent multicore prostate biopsies were recruited from three tertiary centers. Serum markers measured included total PSA (tPSA), free-to-total PSA (f/tPSA), p2PSA, percentage of p2PSA (%p2PSA), and prostate health index (PHI). The association between serum markers and PCa risk was assessed by logistic regression. Predictive performance for each marker was quantified using the area under the receiver operator curves (AUC). Among 516 men, 18.2% had PCa at biopsy. For all tested markers, their predictive value on PCa risk was lower in obese patients compared to normal weight patients. We found statistically significant interactions between BMI and tPSA (P = 0.0026) and p2PSA (P = 0.038). PHI achieved an AUC of 0.872 in normal weight patients and 0.745 in obese patients, which outperformed the other predictors regardless of BMI category. In conclusion, PHI achieved the best predictive performance for detecting PCa and was not influenced by BMI.

Development and external validation of a prostate health index-based nomogram for predicting prostate cancer.

To develop and externally validate a prostate health index (PHI)-based nomogram for predicting the presence of prostate cancer (PCa) at biopsy in Chinese men with prostate-specific antigen 4-10 ng/mL and normal digital rectal examination (DRE). 347 men were recruited from two hospitals between 2012 and 2014 to develop a PHI-based nomogram to predict PCa. To validate these results, we used a separate cohort of 230 men recruited at another center between 2008 and 2013. Receiver operator curves (ROC) were used to assess the ability to predict PCa. A nomogram was derived from the multivariable logistic regression model and its accuracy was assessed by the area under the ROC (AUC). PHI achieved the highest AUC of 0.839 in the development cohort compared to the other predictors (p < 0.001). Including age and prostate volume, a PHI-based nomogram was constructed and rendered an AUC of 0.877 (95% CI 0.813-0.938). The AUC of the nomogram in the validation cohort was 0.786 (95% CI 0.678-0.894). In clinical effectiveness analyses, the PHI-based nomogram reduced unnecessary biopsies from 42.6% to 27% using a 5% threshold risk of PCa to avoid biopsy with no increase in the number of missed cases relative to conventional biopsy decision.

Association Between the Body Mass Index and Prostate Cancer at Biopsy is Modified by Genetic Risk: A Cross-Sectional Analysis in China.

Herein, we aimed to examine whether the association of body mass index (BMI) with prostate cancer (PCa) at biopsy differs according to genetic susceptibility.In a multicenter prospective cohort including 1120 men undergoing diagnostic prostate biopsy in China, we evaluated the interaction between BMI and genetic risk score (GRS) comprising 24 PCa-associated single nucleotide polymorphisms (SNPs), as well as a GRS consisting of 7 SNPs derived from an East-Asian population. The genetic risk was defined as low, intermediate, or high when GRS fell in the first, second, and third tertiles, respectively.We observed a significant interaction between BMI and PCa GRS (Pinteraction = 0.047), suggesting that the predictive value of BMI on PCa was strongly modified by genetic susceptibility. In men with high genetic risk, BMI was an independent predictor of PCa (odds ratio [OR] = 1.167, P = 0.008) after adjusting for conventional risk factors. The relationship between BMI and PCa risk diminished (P = 0.990) in men with low genetic risk. The interaction was more pronounced with the East-Asian GRS (Pinteraction = 0.032), suggesting that the overall GRS interaction most likely occurs through genetic susceptibility in the East-Asian population.Our results suggest that the predictive effect of BMI on the PCa risk is strongly modified by individual genetic susceptibility. The association is more positive among men with high genetic risk for PCa.

Influence of age on predictiveness of genetic risk score for prostate cancer in a Chinese hospital-based biopsy cohort.

BACKGROUND: We investigated whether age influences the predictiveness of genetic risk score (GRS) for prostate cancer (PCa) in a Chinese hospital-based biopsy cohort. METHODS: We included consecutive patients who underwent prostate biopsies in two tertiary centers between 2012 and 2014. GRS was calculated using 24 PCa-associated genetic variants and its predictiveness was assessed by area under curve (AUC). RESULTS: Of 1120 men tested, 724 with prostate-specific antigen (PSA) < 20 ng/ml were selected for further analysis. Patients were divided into 3 groups by age cutoffs at 60 and 70 years. GRS significantly predicted PCa for all patients (AUC: 0.561; 95% CI: 0.514-0.609) and was an independent predictor in multivariate analysis for the 60-70 year-olds (AUC: 0.612, 95% CI: 0.541-0.684), but not for patients aged < 60 years or ≥ 70 years. For PCa with Gleason score ≥ 7, GRS discriminative ability was 0.582 (95% CI=0.527-0.637) for all patients, and 0.647 (95% CI: 0.541-0.684) for the 60-70 year-old group. CONCLUSION: GRS significantly increased clinical prediction of PCa and high-grade disease in Chinese men aged 60-70 years, which implies that men in this age group would benefit most from genetic testing.

Pathological features of localized prostate cancer in China: a contemporary analysis of radical prostatectomy specimens.

There has been a rapid increase in the incidence of prostate cancer in China, especially in areas with boosted economic development. In this study, we analyzed the pathological features of a contemporary series of radical prostatectomy cases. A total of 230 consecutive, whole-mounted radical prostatectomy specimens collected from 2012 to 2014 were reviewed. The median age of the patients was 68 years, and 64.3% of patients presented with prostate specific antigen alone. Pathological examination indicated that a high proportion (77.4%) of patients had intermediate- or high-risk disease according to the Cancer of the Prostate Risk Assessment Post-Surgical score. After surgery, only 28 patients met the criteria for active surveillance (organ-confined Gleason ≥6 disease). The Prostate Cancer Research International Active Surveillance criteria achieved a sensitivity of 57.1% and a specificity of 98.0% for identifying candidates. The probability of Gleason score upgrading was 24.8% in the entire group and 59.0% in biopsy-confirmed Gleason ≥6 disease. The predominant tumor was located in the transition zone in 14.8% of cases, while only three patients (1.3%) had a predominant tumor located in the anterior region. Patients with transition zone-predominant tumor were likely to have been referred with urinary symptoms and high prostate specific antigen levels. The results of this study highlight the contemporary pathological features of localized prostate cancer in urban China. There was an increased trend towards asymptomatic cases, though most patients had intermediate- or high-risk disease and were suitable for definitive treatment. The low prevalence of dominant cancer in the anterior region may reflect race-based pathological differences.

The association between metabolic syndrome and advanced prostate cancer in Chinese patients receiving radical prostatectomy.

The global incidence of metabolic syndrome (MetS) is dramatically increasing. Considerable interest has been devoted to the relationship between MetS and prostate cancer (PCa) risk. However, few studies have examined the association between MetS and PCa progression. This retrospective study consisted of 1016 patients with PCa who received radical prostatectomy. The association between MetS and pathological features was evaluated using logistic regression analysis. Compared with patients without MetS, those with MetS indicated an increased risk of prostatectomy Gleason score (GS) ≥8 (odds ratio [OR] =1.670, 95% confidence interval (CI) 1.096-2.545, P= 0.017), and a 1.5-fold increased risk of pT3-4 disease (OR = 1.583, 95% CI 1.106-2.266, P= 0.012). The presence of MetS was an independent predictor of lymph node involvement (OR = 1.751, 95% CI 1.038-2.955, P= 0.036). Furthermore, as the number of MetS components accumulated, the risk of a GS ≥ 8 increased. The present study indicates a significant association between MetS and advanced PCa. The results need to be evaluated in large-scale prospective cohorts.