The Impact of Prostate-Specific Antigen Screening on Prostate Cancer Incidence and Mortality in China: 13-Year Prospective Population-Based Cohort Study.

BACKGROUND: The status of prostate-specific antigen (PSA) screening is unclear in China. Evidence regarding the optimal frequency and interval of serial screening for prostate cancer (PCa) is disputable. OBJECTIVE: This study aimed to depict the status of PSA screening and to explore the optimal screening frequency for PCa in China. METHODS: A 13-year prospective cohort study was conducted using the Chinese Electronic Health Records Research in Yinzhou study's data set. A total of 420,941 male participants aged ≥45 years were included between January 2009 and June 2022. Diagnosis of PCa, cancer-specific death, and all-cause death were obtained from the electronic health records and vital statistic system. Hazard ratios (HRs) with 95% CIs were estimated using Cox regression analysis. RESULTS: The cumulative rate of ever PSA testing was 17.9% with an average annual percent change (AAPC) of 8.7% (95% CI 3.6%-14.0%) in the past decade in China. People with an older age, a higher BMI, higher waist circumference, tobacco smoking and alcohol drinking behaviors, higher level of physical activity, medication use, and comorbidities were more likely to receive PSA screening, whereas those with a lower education level and a widowed status were less likely to receive the test. People receiving serial screening ≥3 times were at a 67% higher risk of PCa detection (HR 1.67; 95% CI 1.48-1.88) but a 64% lower risk of PCa-specific mortality (HR 0.36; 95% CI 0.18-0.70) and a 28% lower risk of overall mortality (HR 0.72; 95% CI 0.67-0.77). People following a serial screening strategy at least once every 4 years were at a 25% higher risk of PCa detection (HR 1.25; 95% CI 1.13-1.36) but 70% (HR 0.30; 95% CI 0.16-0.57) and 23% (HR 0.77; 95% CI 0.73-0.82) lower risks of PCa-specific and all-cause mortality, respectively. CONCLUSIONS: This study reveals a low coverage of PSA screening in China and provides the first evidence of its benefits in the general Chinese population. The findings of this study indicate that receiving serial screening at least once every 4 years is beneficial for overall and PCa-specific survival. Further studies based on a nationwide population and with long-term follow-up are warranted to identify the optimal screening interval in China.

Risk of second primary cancers after a diagnosis of first primary cancer: A pan-cancer analysis and Mendelian randomization study.

Background: The risk of second primary cancers (SPC) is increasing after the first primary cancers (FPC) are diagnosed and treated. The underlying causal relationship remains unclear. Methods: We conducted a pan-cancer association (26 cancers) study in the Surveillance, Epidemiology, and End Results (SEER) database (non-Hispanic whites). The standardized incidence ratio (SIR) was estimated as the risk of SPCs in cancer survivors based on the incidence in the general population. Furthermore, the causal effect was evaluated by two-sample Mendelian Randomization (MR, 13 FPCs) in the UK Biobank (UKB, n=459,136,, European whites) and robust analysis (radial MR and Causal Analysis Using Summary Effect estimates, CAUSE). Results: We found 11 significant cross-correlations among different cancers after harmonizing SIR and MR results. Whereas only 4 of them were confirmed by MR to have a robust causal relationship. In particular, patients initially diagnosed with oral pharyngeal cancer would have an increased risk of non-Hodgkin lymphoma (SIRSEER = 1.18, 95%Confidence Interval [CI]:1.05-1.31, ORradial-MR=1.21, 95% CI:1.13-1.30, p=6.00 × 10-3; ORcause = 1.17, 95% CI:1.05-1.31, p=8.90 × 10-3). Meanwhile, ovary cancer was identified to be a risk factor for soft tissue cancer (SIRSEER = 1.72, 95%Confidence Interval [CI]:1.08-2.60, ORradial-MR=1.39, 95% CI:1.22-1.58, p=1.07 × 10-3; ORcause = 1.36, 95% CI:1.16-1.58, p=0.01). And kidney cancer was likely to cause the development of lung cancer (SIRSEER = 1.28, 95%Confidence Interval [CI]:1.22-1.35, ORradial-MR=1.17, 95% CI:1.08-1.27, p=6.60 × 10-3; ORcause = 1.16, 95% CI:1.02-1.31, p=0.05) and myeloma (SIRSEER = 1.54, 95%Confidence Interval [CI]:1.33-1.78, ORradial-MR=1.72, 95% CI:1.21-2.45, p=0.02; ORcause = 1.49, 95% CI:1.04-2.34, p=0.02). Conclusions: A certain type of primary cancer may cause another second primary cancer, and the profound mechanisms need to be studied in the future. Funding: This work was in supported by grants from National Natural Science Foundation of China (Grant No. 81972645), Innovative research team of high-level local universities in Shanghai, Shanghai Youth Talent Support Program, intramural grant of The University of Hong Kong to Dr. Rong Na, and Shanghai Sailing Program (22YF1440500) to Dr. Da Huang.

Better cancer treatment and early detection have increased survival rates among patients with cancer. But some cancer survivors can develop a second cancer called a second primary cancer. Second primary cancers may occur months or years after successful treatment of the primary cancer. They are not caused by the spread of the original tumor like a cancer metastasis. Instead, they appear to occur independently in another location or tissue. Scientists are trying to understand what causes second primary cancers. Genetics, lifestyle, the environment, treatments used for the initial tumor, or other factors may all contribute to individuals developing a second cancer. Learning more about who is at risk of developing a second cancer and why, may lead to new prevention, treatment or screening strategies. Ruan, Huang et al. found that people with some primary cancers have an increased risk of secondary primary cancers in specific tissues. The researchers first looked at the Surveillance, Epidemiology, and End Results (SEER) database that tracks US cancer patients to see if different types of cancers were more likely to lead to a second primary cancer. Then, the team conducted a comprehensive analysis for a causal relationship in a second extensive health database, the UK Biobank, to determine if the primary cancers may have caused the second primary cancer. The study showed that patients diagnosed with mouth or throat cancers were at increased risk of later developing a lymph node cancer called non-Hodgkin lymphoma. Patients diagnosed with ovarian cancer were at increased risk of later developing cancer in one of the body's soft tissues. Kidney cancer is likely the cause of later lung cancers and a type of blood cancer called myeloma. Understanding the relationships between an initial and later cancer diagnosis is essential to improve cancer survivors' care. It is especially important for patients diagnosed early in life. More studies are needed to confirm the links Ruan, Huang et al. identified and to understand the mechanism. If more studies confirm the associations, physicians may want to screen survivors for specific cancers. Scientists may also be able to use the information to develop new strategies to help prevent or treat secondary primary cancers.

Genetic risk assessment of lethal prostate cancer using polygenic risk score and hereditary cancer susceptibility genes.

BACKGROUND: The genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate volume (PV) is a potential well-established risk factor for aggressive PCa, we hypothesize that polygenic risk score (PRS) based on benign prostate hyperplasia (BPH) or PV-related SNPs may also predict the risk of aggressive PCa or PCa death. METHODS: We evaluated a PRS using 21 BPH/PV-associated SNPs, two established PCa risk-related PRS and 10 guideline-recommended hereditary cancer risk genes in the population-based UK Biobank cohort (N = 209,502). RESULTS: The BPH/PV PRS was significantly inversely associated with the incidence of lethal PCa as well as the natural progress in PCa patients (hazard ratio, HR = 0.92, 95% confidence interval [CI]: 0.87-0.98, P = 0.02; HR = 0.92, 95% CI 0.86-0.98, P = 0.01). Compared with men at the top 25th PRS, PCa patients with bottom 25th PRS would have a 1.41-fold (HR, 95% CI 1.16-1.69, P = 0.001) increased PCa fatal risk and shorter survival time at 0.37 yr (95% CI 0.14-0.61, P = 0.002). In addition, patients with BRCA2 or PALB2 pathogenic mutations would also have a high risk of PCa death (HR = 3.90, 95% CI 2.34-6.51, P = 1.79 × 10-7; HR = 4.29, 95% CI 1.36-13.50, P = 0.01, respectively). However, no interactive but independent effects were detected between this PRS and pathogenic mutations. CONCLUSIONS: Our findings provide a new measurement of PCa patients' natural disease outcomes via genetic risk ways.

Genetic Polymorphisms of the Telomerase Reverse Transcriptase Gene in Relation to Prostate Tumorigenesis, Aggressiveness and Mortality: A Cross-Ancestry Analysis.

BACKGROUND: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. METHODS: Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). RESULTS: A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12-1.20, p = 4.12 × 10-16) and rs11291391 (OR = 1.73, 95%CI:1.34-2.25, p = 3.04 × 10-5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31-1.71, p = 2.91 × 10-9) and rs2853677 (OR = 1.74, 95%CI:1.52-1.98, p = 3.52 × 10-16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04-2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10-15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171). CONCLUSION: TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries.

Causal Effects of Modifiable Behaviors on Prostate Cancer in Europeans and East Asians: A Comprehensive Mendelian Randomization Study.

OBJECTIVE: Early evidence is disputable for the effects of modifiable lifestyle behaviors on prostate cancer (PCa) risk. No research has yet appraised such causality in different ancestries using a Mendelian randomization (MR) approach. METHODS: A two-sample univariable and multivariable MR analysis was performed. Genetic instruments associated with lifestyle behaviors were selected based on genome-wide association studies. Summary-level data for PCa were obtained from PRACTICAL and GAME-ON/ELLIPSE consortia for Europeans (79,148 PCa cases and 61,106 controls), and ChinaPCa consortium for East Asians (3343 cases and 3315 controls). Replication was performed using FinnGen (6311 cases and 88,902 controls) and BioBank Japan data (5408 cases and 103,939 controls). RESULTS: Tobacco smoking was identified as increasing PCa risks in Europeans (odds ratio [OR]: 1.95, 95% confidence interval [CI]: 1.09-3.50, p = 0.027 per standard deviation increase in the lifetime smoking index). For East Asians, alcohol drinking (OR: 1.05, 95%CI: 1.01-1.09, p = 0.011) and delayed sexual initiation (OR: 1.04, 95%CI: 1.00-1.08, p = 0.029) were identified as risk factors, while cooked vegetable consumption (OR: 0.92, 95%CI: 0.88-0.96, p = 0.001) was a protective factor for PCa. CONCLUSIONS: Our findings broaden the evidence base for the spectrum of PCa risk factors in different ethnicities, and provide insights into behavioral interventions for prostate cancer.

Socioeconomic determinants are associated with the utilization and outcomes of active surveillance or watchful waiting in favorable-risk prostate cancer.

BACKGROUND: Active surveillance/watchful waiting (AS/WW) is feasible and effective for favorable-risk prostate cancer (PCa). Understanding socioeconomic determinants of AS/WW may help determine the target population for social support and improve cancer-related survival. METHODS: The Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting Database 18 Registries identified 229,428 adult men diagnosed with primary localized PCa (clinical T1-T2c, N0M0) during a median follow-up of 45 months between 2010 and 2016. Socioeconomic determinants included socioeconomic status (SES) tertiles, marital status (unmarried vs married), and residency (urban vs rural). Multivariable logistic regression and Cox models determined the adjusted odds ratios (aOR) for AS/WW utilization, and adjusted hazard ratio (aHR) for cancer-specific survival (CSS) and overall survival (OS). The extent of missing data was evaluated by multiple imputation. Sensitivity analyses were performed in multiple imputation datasets. RESULTS: Unmarried patients were more likely to receive AS/WW in low-risk group (aOR, 1.20 [95%CI, 1.12-1.28]; p < 0.001) and favorable intermediate-risk group (aOR, 1.41 [95%CI, 1.26-1.59]; p < 0.001) than married patients. Urban patients had 0.77-fold lower likelihood of AS/WW than rural patients in low-risk group (95% CI, 0.68-0.87; p < 0.001), but not in favorable intermediate-risk groups. Among patients undertaking AS/WW, a significantly worse OS was observed among unmarried patients comparing to married group (aHR, 1.98 [95% CI, 1.50-2.60]; p < 0.001), and patients with high SES had better CSS than low group (aHR, 0.08 [95%CI, 0.01-0.69]; p = 0.02). No significant survival difference was found between urban and rural patients. CONCLUSIONS AND RELEVANCE: Unmarried or urban patients had significantly higher rates of AS/WW. The utilization and efficacy of conservative management were affected by socioeconomic factors, which might serve as a barrier of treatment decision-making and targeted a population in need of social support.

The Combined Effect of Polygenic Risk Score and Prostate Health Index in Chinese Men Undergoing Prostate Biopsy.

To date, the combined effect of polygenic risk score (PRS) and prostate health index (phi) on PCa diagnosis in men undergoing prostate biopsy has never been investigated. A total of 3166 patients who underwent initial prostate biopsy in three tertiary medical centers from August 2013 to March 2019 were included. PRS was calculated on the basis of the genotype of 102 reported East-Asian-specific risk variants. It was then evaluated in the univariable or multivariable logistic regression models that were internally validated using repeated 10-fold cross-validation. Discriminative performance was assessed by area under the receiver operating curve (AUC) and net reclassification improvement (NRI) index. Compared with men in the first quintile of age and family history adjusted PRS, those in the second, third, fourth, and fifth quintiles were 1.86 (odds ratio, 95% confidence interval (CI): 1.34-2.56), 2.07 (95%CI: 1.50-2.84), 3.26 (95%CI: 2.36-4.48), and 5.06 (95%CI: 3.68-6.97) times as likely to develop PCa (all p < 0.001). Adjustment for other clinical parameters yielded similar results. Among patients with prostate-specific antigen (PSA) at 2-10 ng/mL or 2-20 ng/mL, PRS still had an observable ability to differentiate PCa in the group of prostate health index (phi) at 27-36 (Ptrend < 0.05) or >36 (Ptrend ≤ 0.001). Notably, men with moderate phi (27-36) but highest PRS (top 20% percentile) would have a comparable risk of PCa (positive rate: 26.7% or 31.3%) than men with high phi (>36) but lowest PRS (bottom 20% percentile positive rate: 27.4% or 34.2%). The combined model of PRS, phi, and other clinical risk factors provided significantly better performance (AUC: 0.904, 95%CI: 0.887-0.921) than models without PRS. Adding PRS to clinical risk models could provide significant net benefit (NRI, from 8.6% to 27.6%), especially in those early onset patients (NRI, from 29.2% to 44.9%). PRS may provide additional predictive value over phi for PCa. The combination of PRS and phi that effectively captured both clinical and genetic PCa risk is clinically practical, even in patients with gray-zone PSA.

Systematic evaluation of narrow-sense validity of polygenic risk score for prostate cancer in a Chinese prostate biopsy cohort.

The aim of this study was to assess the narrow-sense validity of polygenic risk score (PRS) for prostate cancer (PCa) in a Chinese prostate biopsy cohort. We performed an observational prospective study with 2640 men who underwent prostate biopsy. Germline DNA samples were genotyped and PRS was calculated for each subject using 17 PCa risk-associated genetic variants. Additional GWAS data of the ChinaPCa dataset was also used to compliment the evaluation process. The mean PRS was 1.02 in patients with negative biopsy results, which met the baseline benchmark. The mean PRS was significantly higher in the PCa cases (1.32 vs. 1.02, p = 5.56 × 10-17 ). Significant dose-response associations between PRS values and odds ratios for PCa were observed. However, the raw calibration slope was 0.524 and the average bias score between the observed risk and uncorrected PRS value was 0.307 in the entire biopsy cohort. After applying a correction factor derived from a training set, the corrected calibration slope improved to 1.002 in a testing set. Similar and satisfied results were also seen in the ChinaPCa dataset and two datasets combined, while the calibration results were inaccurate when the calibration process were performed mutually between two different study populations. In conclusion, assessing the narrow-sense validity of PRS is necessary prior to its clinical implementation for accurate individual risk assessment.

CRISPR screening reveals gleason score and castration resistance related oncodriver ring finger protein 19 A (RNF19A) in prostate cancer.

Prostate cancer (PCa) is one of the most lethal causes of cancer-related death in male. It is characterized by chromosomal instability and disturbed signaling transduction. E3 ubiquitin ligases are well-recognized as mediators leading to genomic alterations and malignant phenotypes. There is a lack of systematic study on novel oncodrivers with genomic and clinical significance in PCa. In this study we used clustered regularly interspaced short palindromic repeats (CRISPR) system to screen 656 E3 ubiquitin ligases as oncodrivers or tumor repressors in PCa cells. We identified 51 significantly changed genes, and conducted genomic and clinical analysis on these genes. It was found that the Ring Finger Protein 19 A (RNF19A) was a novel oncodriver in PCa. RNF19A was frequently amplified and highly expressed in PCa and other cancer types. Clinically, higher RNF19A expression correlated with advanced Gleason Score and predicted castration resistance. Mechanistically, transcriptomics, quantitative and ubiquitination proteomic analysis showed that RNF19A ubiquitylated Thyroid Hormone Receptor Interactor 13 (TRIP13) and was transcriptionally activated by androgen receptor (AR) and Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A). This study uncovers the genomic and clinical significance of a oncodriver RNF19A in PCa. The results of this study indicate that targeting AR/HIF1A-RNF19A-TRIP13 signaling axis could be an alternative option for PCa diagnosis and therapy.

Outcomes of radical prostatectomy in a 20-year localized prostate cancer single institution series in China.

The long-term survival outcomes of radical prostatectomy (RP) in Chinese prostate cancer (PCa) patients are poorly understood. We conducted a single-center, retrospective analysis of patients undergoing RP to study the prognostic value of pathological and surgical information. From April 1998 to February 2022, 782 patients undergoing RP at Queen Mary Hospital of The University of Hong Kong (Hong Kong, China) were included in our study. Multivariable Cox regression analysis and Kaplan-Meier analysis with stratification were performed. The 5-year, 10-year, and 15-year overall survival (OS) rates were 96.6%, 86.8%, and 70.6%, respectively, while the 5-year, 10-year, and 15-year PCa-specific survival (PSS) rates were 99.7%, 98.6%, and 97.8%, respectively. Surgical International Society of Urological Pathology PCa grades (ISUP Grade Group) ≥4 was significantly associated with poorer PSS (hazard ratio [HR] = 8.52, 95% confidence interval [CI]: 1.42-51.25, P = 0.02). Pathological T3 stage was not significantly associated with PSS or OS in our cohort. Lymph node invasion and extracapsular extension might be associated with worse PSS (HR = 20.30, 95% CI: 1.22-336.38, P = 0.04; and HR = 7.29, 95% CI: 1.22-43.64, P = 0.03, respectively). Different surgical approaches (open, laparoscopic, or robotic-assisted) had similar outcomes in terms of PSS and OS. In conclusion, we report the longest timespan follow-up of Chinese PCa patients after RP with different approaches.

Application of European-specific polygenic risk scores for predicting prostate cancer risk in different ancestry populations.

BACKGROUND: Polygenic risk score (PRS) has shown promise in predicting prostate cancer (PCa) risk. However, the application of PRS in non-European ancestry was poorly studied. METHODS: We constructed PRS using 68, 86, or 128 PCa-associated single-nucleotide polymorphisms (SNPs) identified through a large-scale Genome-wide association study (GWAS) in the European ancestry population. A calibration approach was performed to adjust the PRS exact value for each ancestry. The study was conducted in East Asian (ChinaPCa Consortium, n = 2379), European (UK Biobank, n = 209,172), and African American (African Ancestry Prostate Cancer Consortium, n = 6016). RESULTS: Individuals with the highest PRS (in >97.5th percentile) had over 2.5-fold increased risk of PCa than those with average PRS (in 40th-60th percentile) in both European (odds ratio [OR] = 3.79, 95% confidence interval [CI] = 3.46-4.16, p < 0.001) and Chinese (OR = 2.87, 95% CI = 1.29-6.40, p = 0.010), while slightly lower in African American (OR = 1.77, 95% CI = 1.22-2.58, p = 0.008). Compared with the lowest PRS (in <2.5th percentile), increased PRS was also associated with the earlier onset of PCa (All log-rank p < 0.05). The highest PRS contributed to having about 5- to 12-fold higher lifetime risk and 5-10 years earlier at disease onset than the lowest category across different ancestry populations. CONCLUSION: We demonstrated that European-GWAS-based PRS could also significantly predict PCa risk in Asian ancestry and African ancestry populations.

Association between cannabis use with urological cancers: A population-based cohort study and a mendelian randomization study in the UK biobank.

BACKGROUND: Legislation of cannabis use has been approved in many European and North American countries. Its impact on urological cancers is unclear. This study was conducted to explore the association between cannabis use and the risk of urological cancers. METHODS: We identified 151,945 individuals with information on cannabis use in the UK Biobank from 2006 to 2010. Crude and age-standardized incidence ratios of different urological cancers were evaluated in the entire cohort and subgroups. Cox regression was performed for survival analysis. RESULTS: Previous use of cannabis was a significant protective factor for renal cell carcinoma (HR = 0.61, 95%CI:0.40-0.93, p = 0.021) and prostate cancer (HR = 0.82, 95%CI:0.73-0.93, p = 0.002) in multivariable analysis. The association between previous cannabis use and both renal cell carcinoma and bladder cancer was only observed in females (HRRCC  = 0.42, 95%CI:0.19-0.94, p = 0.034; HRBCa  = 0.43, 95%CI:0.21-0.86, p = 0.018) but not in men. There was no significant association between cannabis use and testicular cancer incidence. Mendelian randomization demonstrated a potential causal effect of cannabis use on a lower incidence of renal cell carcinoma. CONCLUSIONS: Previous use of cannabis was associated with a lower risk of bladder cancer, renal cell carcinoma, and prostate cancer. The inverse association between cannabis and both renal cell carcinoma and bladder cancer was only found in females but not in males.

Clinical translational research of liquid biopsy applications in prostate cancer and other urological cancers.

The aim of liquid biopsies is to obtain tumor information via the molecular interrogation of liquid samples, including blood and urine. As a minimally invasive procedure, liquid biopsies have attracted attention. A series of studies have reported associations of biomarkers such as circulating tumor DNA, cell-free DNA and extracellular vesicles with urological cancers, especially prostate cancer (PCa), and demonstrated the promising potential of liquid biopsies. In this review, we summarize recent clinical translational studies of liquid biopsies in PCa and other urological cancers, including bladder cancer and renal cell carcinoma. The number of translational studies was limited, and most of the studies focused on PCa. Biomarkers isolated from blood by different detection methods could be applied in clinical practice to predict prognosis and treatment response in advanced PCa. The other applications in urological cancers identified in previous studies remain to be explored further. Current studies are limited due to the lack of ideal standard detection methods for biomarkers. In the future, with advances in methodology, more translational studies will be conducted to identify potential applications of liquid biopsies in urological cancers.

Exploration of the cancer genome atlas database reveals genes of interest related with cancer cell stemness indices in clear cell renal cell carcinoma.

Heterogeneity of kidney cancer poses great challenges in clinical management. Practicians are still in need of an effective way to identify high-risk patients. Here we browsed big data from The Cancer Genome Atlas database with reference to cancer cell stemness and identified genes of interest in clear cell renal cell carcinoma. We further analyzed these genes to uncover their role in cancer promotion and progression and presented an interaction network. The results highlighted the NOTCH signaling pathway and functions related with epithelial cell migration. Finally, we managed to construct a predictive model consisting of a reasonable number of genes that successfully recognized patients at higher risk, rendering these genes suitable as subjects in future research.

Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG.

Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.

The diagnostic value of rapid urine test platform UF-5000 for suspected urinary tract infection at the emergency department.

Background and objective: Urine culture is time consuming, which may take days to get the results and impede further timely treatment. Our objective is to evaluate whether the fast urinalysis and bacterial discrimination system called Sysmex UF-5000 may predict urinary tract infections (UTIs) (within minutes) compared with the clinical routine test in suspected UTI patients. In addition, we aimed to explore the accuracy of microbiologic information by UF-5000. Materials and Methods: Consecutive patients who were admitted from the emergency department at Queen Mary Hospital (a tertiary hospital in Hong Kong) from June 2019 to February 2020 were enrolled in the present study. The dipstick test, manual microscopic test with culture, and Sysmex UF-5000 test were performed in the urine samples at admission. Results: A total of 383 patients were finally included in the present study. UF-5000 urinalysis (area under the receiver operator characteristic curve, AUC=0.821, confidence interval, 95%CI: 0.767-0.874) outperformed the dipstick test (AUC=0.602, 95%CI: 0.550-0.654, P=1.32×10-10) for predicting UTIs in patients without prior antibiotic treatment. A significant net benefit from UF-5000 was observed compared with the dipstick test (NRI=39.9%, 95%CI: 19.4-60.4, P=1.36 × 10-4). The urine leukocyte tested by UF-5000 had similar performance (AUC) for predicting UTI compared with the manual microscopic test (P=0.27). In patients without a prior use of antibiotics, the concordance rates between UF-5000 and culture for predicting Gram-positive or -negative bacteriuria and a negative culture were 44.7% and 96.2%, respectively. Conclusions: UF-5000 urinalysis had a significantly better predictive value than the dipstick urine test for predicting UTIs.

Family History of Cancers Increases Risk of Renal Cell Carcinoma in a Chinese Population.

Purpose: To explore the impact of family history (FH) on renal cell carcinoma (RCC) and its pathological subtype clear cell RCC (ccRCC) in a Chinese population; a significant association has previously been determined not only in familial cancer syndrome but also in sporadic cases in western populations. Methods: Consecutive patients with kidney tumors from October 2017 to May 2021 at a tertiary hospital in Shanghai were enrolled in the study. Demographic and clinical information was collected, including age, gender, FH (positive or negative, types of cancers, degree of relatives, etc.), pathological diagnosis, and Fuhrman grades. Results: A positive FH of any cancer was observed in 26.5% of the RCC patients, while only 16.8% patients with benign kidney tumor were found to have a positive FH. A strong correlation was observed between FH of any cancers in first-degree relatives and RCC (odds ratio [OR]=4.60, 95% confidence interval [CI]: 1.95-10.85, P=5.50×10-5) or ccRCC (OR=4.63, 95% CI: 1.95-11.02, P=9.63×10-5). In subgroup analysis, FH of digestive cancers was significantly associated with RCC (OR=4.42, 95% CI: 1.35-14.51, P=0.005) or ccRCC (OR=4.14, 95% CI: 1.25-13.75, P=6.84×10-4). Similar results were found in multivariate analyses. However, no significant association was observed between FH and age at onset. Conclusion: FH was an independent risk factor for RCC and ccRCC in this Chinese population. FH of any cancer in first-degree relatives and FH of digestive cancers were found to be the most significant risk factors for kidney cancers.

Genome-Wide 3'-UTR Single Nucleotide Polymorphism Association Study Identifies Significant Prostate Cancer Risk-Associated Functional Loci at 8p21.2 in Chinese Population.

MicroRNAs (miRNAs) are involved in the regulation of gene expression via incomplete base pairing to sequence motifs at the three prime untranslated regions (3'-UTRs) of mRNAs and play critical roles in the etiology of cancers. Single nucleotide polymorphisms (SNPs) in the 3'-UTR miRNA-binding regions may influence the miRNA affinity. However, this biological mechanism in prostate cancer (PCa) remains unclear. Here, a three-stage genome-wide association study of 3'-UTR SNPs (n=33 117) is performed in 5515 Chinese men. Three genome-wide significant variants are discovered at 8p21.2 (rs1567669, rs4872176, and rs4872177), which are all located in a linkage disequilibrium region of the NKX3-1 gene. Phenome-wide association analysis using the FinnGen data reveals a specific association of rs1567669 with PCa over 2,264 disease endpoints. Expression quantitative trait locus analyses based on both Chinese PCa cohort and the GTEx database show that risk alleles of these SNPs are significantly associated with low expression of NKX3-1. Based on the MirSNP database, dual-luciferase reporter assays show that risk alleles of these SNPs downregulate the expression of NKX3-1 via increased miRNA binding. These results indicate that the SNPs at the 3'-UTR of NKX3-1 significantly downregulate NKX3-1 expression by influencing the affinity of miRNA and increase the PCa risk.

Prostate Health Index (phi) and its derivatives predict Gleason score upgrading after radical prostatectomy among patients with low-risk prostate cancer.

To analyze the performance of the Prostate Health Index (phi) and its derivatives for predicting Gleason score (GS) upgrading between prostate biopsy and radical prostatectomy (RP) in the Chinese population, an observational, prospective RP cohort consisting of 351 patients from two medical centers was established from January 2017 to September 2020. Pathological reclassification was determined by the Gleason Grade Group (GG). The area under the receiver operating characteristic curve (AUC) and logistic regression (LR) models were used to evaluate the predictive performance of predictors. In clinically low-risk patients with biopsy GG ≤2, phi (odds ratio [OR] = 1.80, 95% confidence interval [95% CI]: 1.14-2.82, P = 0.01) and its derivative phi density (PHID; OR = 2.34, 95% CI: 1.30-4.20, P = 0.005) were significantly associated with upgrading to GG ≥3 after RP, and the results were confirmed by multivariable analysis. Similar results were observed in patients with biopsy GG of 1 for the prediction of upgrading to RP GG≥2. Compared to the base model (AUC = 0.59), addition of the phi or PHID could provide additional predictive value for GS upgrading in low-risk patients (AUC = 0.69 and 0.71, respectively, both P < 0.05). In conclusion, phi and PHID could predict GS upgrading after RP in clinically low-risk patients.