Yishuo Wu

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

BACKGROUNDnGermline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk.nnnOBJECTIVEnTo directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death.nnnDESIGN, SETTING, AND PARTICIPANTSnA retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnMutation carrier rates and their effect on lethal PCa were analyzed using the Fishers exact test and Cox regression analysis, respectively.nnnRESULTS AND LIMITATIONSnThe combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed.nnnCONCLUSIONSnMutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time.nnnPATIENT SUMMARYnProstate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

Performance of serum prostate-specific antigen isoform [-2]proPSA (p2PSA) and the prostate health index (PHI) in a Chinese hospital-based biopsy population

The use of serum [‐2]proPSA (p2PSA) and its derivative, the prostate health index (PHI), in detecting prostate cancer (PCa) have been consistently shown to have better performance than total prostate‐specific antigen (tPSA) in discriminating biopsy outcomes in western countries. However, little is known about their performance in Chinese men. Our objective is to test the performance of p2PSA and PHI and their added value to tPSA in discriminating biopsy outcomes in Chinese men.

Prediction of prostate cancer from prostate biopsy in Chinese men using a genetic score derived from 24 prostate cancer risk-associated SNPs.

Twenty‐four prostate cancer (PCa) risk‐associated single nucleotide polymorphisms (SNPs) in Chinese men have been cataloged. We evaluated whether these SNPs can independently predict outcomes of prostate biopsy, and improve the predictive performance of existing clinical variables.

Plateau effect of prostate cancer risk-associated SNPs in discriminating prostate biopsy outcomes.

Additional prostate cancer (PCa) risk‐associated single nucleotide polymorphisms (SNPs) continue to be identified. It is unclear whether addition of newly identified SNPs improves the discriminative performance of biopsy outcomes over previously established SNPs.

Outcomes and trends of prostate biopsy for prostate cancer in Chinese men from 2003 to 2011.

Background Prostate-specific antigen (PSA) screening is growing in popularity in China, but its impact on biopsy characteristics and outcomes are poorly understood. Objective Our objective was to characterize prostate biopsy outcomes and trends in Chinese men over a 10-year period, since the increasing use of PSA tests. Methods All men (nu200a=u200a1,650) who underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China from 2003–2011 were evaluated. Demographic and clinical information was collected for each patient, including age, digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total prostate-specific antigen (tPSA) levels and free PSA ratio (fPSA/tPSA) prior to biopsy. Prostate biopsy was performed using six cores before October 2007 or ten cores thereafter. Logistic regression and multivariate analysis were used to evaluate our data. Results The overall positive rate of prostate biopsy for PCa was 47% and the rate decreased significantly over the years from 74% in 2003 to 33% in 2011 (P-trendu200a=u200a0.004) . Age at diagnosis was slightly increased (P-trendu200a=u200a0.04) while fPSA/tPSA was significantly decreased (P-trendu200a=u200a1.11×10-5). A statistically significant trend was not observed for tPSA levels, prostate volume, or proportion of positive nodule. The model including multiple demographic and clinical variables (i.e., age, DRE, tPSA, fPSA/tPSA and transrectal ultrasound results) (AUCu200a=u200a0.93) statistically outperformed models that included only PSA (AUCu200a=u200a0.85) or fPSA/tPSA (AUCu200a=u200a0.66) to predict PCa risks (P<0.05). Similar results were observed in a subgroup of men whose tPSA levels were lower than 20 ng/mL (AUCu200a=u200a0.87, vs. AUC of tPSA u200a=u200a0.62, P<0.05). Conclusions Detection rates of PCa and high-grade PCa among men that underwent prostate biopsy at the institution has decreased significantly in the past 10 years, likely due to increasing use of PSA tests. Predictive performance of demographic and clinical variables of PCa was excellent. These variables should be used in clinics to determine the need for prostate biopsy.

Plasma genistein and risk of prostate cancer in Chinese population.

ObjectivesGenistein is one of the main soy isoflavones in our daily diet. There were studies proving that high-dietary intake of genistein may relate to the low morbidity and mortality of prostate cancer (PCa) in the Asian population. Since there were few studies of plasma genistein level in the Chinese population, we performed this study to preliminarily evaluate the associations among plasma genistein, epidemiologic factors and PCa in a Chinese population.MethodsBetween 2012 and 2013, 100 men over the age of 40 underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China. Clinical information, epidemiologic information and blood samples were collected prior to biopsy for each patient. All patients underwent 10-core ultrasound-guided transperineal prostate biopsy, and the pathology results were collected after biopsy. We measured the plasma genistein concentration of the blood samples and analyzed the results along with the clinical and epidemiologic information.ResultsAmong the 100 patients, 46 (46.0xa0%) were diagnosed with PCa. The median plasma genistein concentration of non-PCa patients (728.6xa0ng/ml) was significantly higher than that of PCa patients (513.0xa0ng/ml) (Pxa0<xa00.05). In the univariate analysis, we found that age and smoking history were related to PCa (Pxa0<xa00.05). In the multivariate analysis, we found that age, smoking history and plasma genistein were related to PCa (Pxa0<xa00.05). The age-adjusted odds ratio of PCa risk comparing plasma genistein level above median to that below median was 0.31 (95xa0% CI 0.13–0.71).ConclusionOur study suggested that high concentration of plasma genistein level may contribute to the low incidence of prostate cancer in Chinese population.

Age-Specific Prostate Specific Antigen Cutoffs for Guiding Biopsy Decision in Chinese Population

Background Age-specific prostate specific antigen (PSA) cutoffs for prostate biopsy have been widely used in the USA and European countries. However, the application of age-specific PSA remains poorly understood in China. Methods Between 2003 and 2012, 1,848 men over the age of 40, underwent prostate biopsy for prostate cancer (PCa) at Huashan Hospital, Shanghai, China. Clinical information and blood samples were collected prior to biopsy for each patient. Men were divided into three age groups (≤60, 61 to 80, and >80) for analyses. Digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total PSA (tPSA), and free PSA (fPSA) were also included in the analyses. Logistic regression was used to build the multi-variate model. Results Serum tPSA levels were age-dependent (Pu200a=u200a0.008), while %fPSA (Pu200a=u200a0.051) and PSAD (Pu200a=u200a0.284) were age-independent. At a specificity of 80%, the sensitivities for predicting PCa were 83%, 71% and 68% with tPSA cutoff values of 19.0 ng/mL (age≤60),21.0 ng/mL (age 61–80), and 23.0 ng/mL (age≥81). Also, sensitivities at the same tPSA levels were able to reach relatively high levels (70%–88%) for predicting high-grade PCa. Area (AUC) under the receive operating curves (ROCs) of tPSA, %fPSA, PSAD and multi-variate model were different in age groups. When predicting PCa, the AUC of tPSA, %fPSA, PSAD and multi-variate model were 0.90, 0.57, 0.93 and 0.87 respectively in men ≤60 yr; 0.82, 0.70, 0.88 and 0.86 respectively in men 61–80 yr; 0.79, 0.78, 0.87 and 0.88 respectively in men>80 yr. When predicting Gleason Score ≥7 or 8 PCa, there were no significant differences between AUCs of each variable. Conclusion Age-specific PSA cutoff values for prostate biopsy should be considered in the Chinese population. Indications for prostate biopsies (tPSA, %fPSA and PSAD) should be considered based on age in the Chinese population.

The Evaluation of the Risk Factors for Non-Muscle Invasive Bladder Cancer (NMIBC) Recurrence after Transurethral Resection (TURBt) in Chinese Population

Objective The risk factors of bladder cancer recurrence after transurethral resection of bladder tumor (TURBt) were poorly understood, especially in Chinese population. This study evaluated the potential risk factors of recurrence based on a Chinese population. Materials and Methods A total of 698 patients that received TURBt procedure in our institute from 2000 to 2012 were recruited in this study. Clinical information was collected. The patients were followed up according to the schedule recommended by Chinese guideline. Results A total of 583 males (83.5%) and 115 females (16.5%) were enrolled in our study. The median follow-up duration was 51.5 months. Gender, chief complain, tumor size, number of lesions, histological grade and chemotherapeutic agents were found significantly associated with patients’ short-term recurrence (less than 1 year) (All p<0.05). In the multivariate analysis, tumor size, number of lesions, histological grade and chemotherapeutic agents were significantly related to patients’ short-term recurrence (less than 1 year) (All p<0.05). A multivariate model based on tumor size, number of lesions, histological grade and chemotherapeutic agents had an AUC of 0.697, which significantly improved the prediction utility for bladder cancer short-term recurrence (less than 1 year) than any single factor In the multivariate Cox regression, tumor size greater than 3 cm, multifocal lesions, worsen histological grade and non-urothelial carcinoma was related to time to recurrence (TR). Conclusion Patients with larger tumor size, multifocal number of lesions, higher tumor grade and who received chemotherapeutic agents other than Epirubicin and Pirarubicin might have higher risks of recurrence less than 1 year. Tumor size, number of lesions, pathology and histological grade might be associated with TR. As Bacille Calmette-Guerin (BCG) is currently not approved for bladder cancer in China, Epirubicin and Pirarubicin might be considered prior to other chemotherapy medications when providing post-operative instillation of chemotherapy.

Clinically available RNA profiling tests of prostate tumors: utility and comparison

In the postscreening era, physicians are in need of methods to discriminate aggressive from nonaggressive prostate cancer (PCa) to reduce overdiagnosis and overtreatment. However, studies have shown that prognoses (e.g., progression and mortality) differ even among individuals with similar clinical and pathological characteristics. Existing risk classifiers (TMN grading system, Gleason score, etc.) are not accurately enough to represent the biological features of PCa. Using new genomic technologies, novel biomarkers and classifiers have been developed and shown to add value to clinical or pathological risk factors for predicting aggressive disease. Among them, RNA testing (gene expression analysis) is useful because it can not only reflect genetic variations but also reflect epigenetic regulations. Commercially available RNA profiling tests (Oncotype Dx, Prolaris, and Decipher) have demonstrated strong abilities to discriminate PCa with poor prognosis from less aggressive diseases. For instance, these RNA profiling tests can predict disease progression in active surveillance patients or early recurrence after radical treatments. These tests may offer more dependable methods for PCa prognosis prediction to make more accurate and personal medical decisions.

Higher body mass index increases the risk for biopsy-mediated detection of prostate cancer in Chinese men.

Objective To investigate the relationship between body mass index (BMI) and prostate cancer (PCa) risk at biopsy in Chinese men. Patients and Methods We retrospectively reviewed the records of 1,807 consecutive men who underwent initial multicore (≥10) prostate biopsy under transrectal ultrasound guidance between Dec 2004 and Feb 2014. BMI was categorised based on the Asian classification of obesity as follows: <18.5 (underweight), 18.5–22.9 (normal weight), 23–24.9 (overweight), 25–29.9 (moderately obese), and ≥30 kg/m2 (severely obese). The odds ratios (OR) of each BMI category for risk of PCa and high-grade prostate cancer (HGPCa, Gleason score ≥4+3) detection were estimated in crude, age-adjusted and multivariate-adjusted models. Prevalence ratios and accuracies of PSA predicted PCa were also estimated across BMI groups. Results In total, PCa was detected by biopsy in 750 (45.4%) men, and HGPCa was detected in 419 (25.4%) men. Compared with men of normal weight, underweight men and obese men were older and had higher prostate specific antigen levels. The risk of overall PCa detection via biopsy presented an obvious U-shaped relationship with BMI in crude analysis. Overall, 50.0%, 37.4%, 45.6% 54.4% and 74.1% of the men in the underweight, normal weight, overweight, moderately obese and severely obese groups, respectively, were diagnosed with PCa via biopsy. In multivariate analysis, obesity was significantly correlated with a higher risk of PCa detection (OR = 1.17, 95%CI 1.10–1.25, P<0.001). However, higher BMI was not correlated with HGPCa detection (OR = 1.03, 95%CI 0.97–1.09, P = 0.29). There were no significant differences in the accuracy of using PSA to predict PCa or HGPCa detection across different BMI categories. Conclusion Obesity was associated with higher risk of PCa detection in the present Chinese biopsy population. No significant association was detected between obesity and HGPCa.