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BACKGROUND: Anticipating the postoperative pathological stage and potential for adverse features of prostate cancer (PCa) patients before radical prostatectomy (RP) is crucial for guiding perioperative treatment. METHODS: A cohort consisting of three sub-cohorts with a total of 709 patients has been enlisted from two major tertiary medical centres in China. The primary assessment parameters for adverse pathological features in this study are the pathological T stage, the AJCC prognostic stage groups and perineural invasion (PNI). Logistic regression analyses were performed to investigate the relationship between prostate specific antigen (PSA), its derivatives (incluing Prostate Health Index, phi and phi density, phiD), and the pathological outcomes after RP. RESULTS: Both phi and phiD showed a significant association with pathologic T stage of pT3 or above (phi, adjusted OR, AOR = 2.82, 95% confidence interval, 95% CI: 1.88-4.23, p < 0.001; phiD, AOR = 2.47, 95% CI: 1.76-3.48, p < 0.001) and PNI (phi, AOR = 2.15, 95% CI: 1.39-3.32, p < 0.001; phiD, AOR = 1.94, 95% CI: 1.38-2.73, p < 0.001). In a subgroup analysis with a total PSA value <10 ng/mL, phi and phiD continued to show a significant correlation with pT3 or above (phi, AOR = 4.70, 95% CI: 1.29-17.12, p = 0.019; phiD, AOR = 3.44, 95% CI: 1.51-7.85, p = 0.003), and phiD also maintained its predictive capability for PNI in this subgroup (AOR = 2.10, 95% CI: 1.17-3.80, p = 0.014). Sensitivity analysis indicated that the findings in the combined cohort are mainly influenced by one of the sub-cohorts, partially attributable to disparities in sample sizes between sub-cohorts. Combined analysis of phi(D) and multiparametric MRI (mpMRI) data yielded similar results. CONCLUSIONS: Preoperative measurement of serum phi and phiD is valuable for predicting the occurrence of adverse pathological features in Chinese PCa patients after RP.
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Estadiamento de Neoplasias , Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/sangue , Pessoa de Meia-Idade , China/epidemiologia , Idoso , Prognóstico , Antígeno Prostático Específico/sangue , População do Leste AsiáticoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Pyroptosis, a type of programmed cell death, regulates tumor cell development. However, the role of pyroptosis-related genes (PRGs) in HCC and their association with prognosis are unclear. METHODS: We conducted bioinformatics analysis to identify PRGs in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) patients. Consensus clustering classified patients into different subtypes. We used LASSO regression to established a pyroptosis subtype-related score (PSRS) related to prognosis. OncoPredict identified potential pharmaceuticals based on PSRS. RESULTS: We found 20 HCC-related PRGs in 335 TCGA-LIHC patients. Consensus clustering classified patients into two subtypes. Subtype I had better overall survival and higher response to anti-PD1 treatment. The prognostic model involving 20 genes predicted poorer prognosis for high-PSRS group. The model was validated in two external cohorts. OncoPredict identified 65 potential pharmaceuticals based on PSRS. CONCLUSION: Our investigation revealed a correlation between pyroptosis and HCC. We established PSRS as independent risk factors for predicting prognosis. The study paves the way for using PRGs as prognostic biomarkers and exploring personalized therapy for HCC.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Piroptose , Piroptose/genética , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Prognóstico , Biomarcadores Tumorais/genética , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Biologia Computacional/métodos , Pessoa de Meia-Idade , Perfilação da Expressão GênicaAssuntos
Inibidor p16 de Quinase Dependente de Ciclina , Detecção Precoce de Câncer , Imuno-Histoquímica , Antígeno Ki-67 , Neoplasias do Colo do Útero , Feminino , Humanos , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Detecção Precoce de Câncer/métodos , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Esfregaço Vaginal/métodosRESUMO
ABSTRACT: Systematic prostate biopsy has limitations, such as overdiagnosis of clinically insignificant prostate cancer and underdiagnosis of clinically significant prostate cancer. Magnetic resonance imaging (MRI)-guided biopsy, a promising alternative, might improve diagnostic accuracy. To compare the cancer detection rates of systematic biopsy and combined biopsy (systematic biopsy plus MRI-targeted biopsy) in Asian men, we conducted a retrospective cohort study of men who underwent either systematic biopsy or combined biopsy at two medical centers (Queen Mary Hospital and Tung Wah Hospital, Hong Kong, China) from July 2015 to December 2022. Descriptive statistics were calculated, and univariate and multivariate logistic regression analyses were performed. The primary and secondary outcomes were prostate cancer and clinically significant prostate cancer. A total of 1391 participants were enrolled. The overall prostate cancer detection rates did not significantly differ between the two groups (36.3% vs 36.6%, odds ratio [OR] = 1.01, 95% confidence interval [CI]: 0.81-1.26, P = 0.92). However, combined biopsy showed a significant advantage in detecting clinically significant prostate cancer (Gleason score ≥ 3+4) in patients with a total serum prostate-specific antigen (tPSA) concentration of 2-10 ng ml-1 (systematic vs combined: 11.9% vs 17.5%, OR = 1.58, 95% CI: 1.08-2.31, P = 0.02). Specifically, in the transperineal biopsy subgroup, combined biopsy significantly outperformed systematic biopsy in the detection of clinically significant prostate cancer (systematic vs combined: 12.6% vs 24.0%, OR = 2.19, 95% CI: 1.21-3.97, P = 0.01). These findings suggest that in patients with a tPSA concentration of 2-10 ng ml-1, MRI-targeted biopsy may be of greater predictive value than systematic biopsy in the detection of clinically significant prostate cancer.
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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.
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Detecção Precoce de Câncer , Neoplasias da Próstata , Humanos , Masculino , China/epidemiologia , Estudos de Coortes , Incidência , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Pessoa de Meia-IdadeRESUMO
We previously reported that an interferon (IFN)-inducible protein, BST2, was regulated by the JAK-STAT pathway activated by CD40, and subsequently suppressing hepatitis B virus (HBV) repliaction and transcription. The current research attempted to assess the impact of BST2 on the IFN-treated anti-HBV effect, and explore BST2 variants for predicting pegylated IFN alpha (PegIFNα) therapy response of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Using an HBV-transfected cell model, the function of BST2 on HBV DNA replication and transcription driven by IFN was studied. The potentially functional BST2 variants were selected through a strategy of gene-wide screening. The associations of BST2 variants and polygenic score (PGS) model, which was used to quantify the combined influence of several genetic variants, with treatment response were examined in 2 separate PegIFNα-treated cohorts of 238 and 707 patients with CHB, respectively. We found that overexpression of BST2 improved the anti-HBV activity triggered by IFN-α. Among PegIFNα-treated patients with CHB, BST2_rs9576 was screened out to be significantly correlated with combined response (CR; i.e., HBeAg seroconversion along with HBV DNA level <3.3log10 IU/mL, P = 7.12 × 10-5 ). Additionally, there was a strong correlation between the PGS incorporating BST2_rs9576 and other 5 genetic variations (previously described predictors of therapy response to PegIFNα) and CR (P = 1.81 × 10-13 ), hepatitis B surface antigen (HBsAg) level (P = 0.004), as well as HBsAg decline (P = 0.017). In conclusion, higher BST2 expression responded better to IFN-α treatment. BST2_rs9576 is an effective indicator to forecast therapy response of PegIFNα-treated patients with CHB. The PGS possesses the potential to boost the ability of PegIFNα therapy response.
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Vírus da Hepatite B , Hepatite B Crônica , Humanos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Antígenos E da Hepatite B/uso terapêutico , Antígenos de Superfície da Hepatite B/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Janus Quinases/uso terapêutico , Resultado do Tratamento , DNA Viral/genética , Fatores de Transcrição STAT/uso terapêutico , Transdução de Sinais , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Antígeno 2 do Estroma da Médula ÓsseaRESUMO
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.
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Neoplasias Renais , Neoplasias Pulmonares , Segunda Neoplasia Primária , Feminino , Adolescente , Humanos , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Análise da Randomização Mendeliana , ChinaRESUMO
BACKGROUND: There is a research gap between genetic predisposition, socioeconomic factors, and their interactions on thyroid tumorigenesis. METHODS: Individual and genetic data were obtained from UK Biobank. Logistic regression models were used to evaluate the association between genetic risk, socioeconomic factors, and thyroid cancer (TCa). A stratified analysis was conducted to estimate their joint effects. A two-sample Mendelian randomization (MR) analysis was further used to examine the potential causality. RESULTS: A total of 502,394 participants were included in this study. Three index loci (rs4449583, rs7726159, and rs7725218) of telomerase reverse transcriptase (TERT) were found to be significantly related to incident TCa. Association analyses showed that high genetic risk, low household income, and high education level were independent risk factors, while unemployment and frequent social connection were suggestive risk factors for TCa. Interaction analyses showed that in participants with low genetic risk, low household income was significantly associated with TCa (odds ratio [OR] = 1.56, 95% confidence interval [CI]: 1.00-2.46). In participants with high genetic risk, those with a high education level (OR = 1.32, 95%CI: 1.06-1.65) and frequent social connection (OR = 1.36, 95%CI: 1.02-1.81) had a significantly increased risk of TCa. However, no causal relationship was observed in the MR analysis. CONCLUSION: Interactions exist between genetic risk, household income, education level, and social connection and thyroid cancer.
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We aim to evaluate prostate health index as an additional risk-stratification tool in patients with Prostate Imaging Reporting and Data System score 3 lesions on multiparametric magnetic resonance imaging. Men with biochemical or clinical suspicion of having prostate cancer who underwent multiparametric magnetic resonance imaging in two tertiary centers (Queen Mary Hospital and Princess Margaret Hospital, Hong Kong, China) between January 2017 and June 2022 were included. Ultrasound-magnetic resonance imaging fusion biopsies were performed after prostate health index testing. Those who only had Prostate Imaging Reporting and Data System score 3 lesions were further stratified into four prostate health index risk groups and the cancer detection rates were analyzed. Out of the 747 patients, 47.3% had Prostate Imaging Reporting and Data System score 3 lesions only. The detection rate of clinically significant prostate cancer in this group was 15.0%. The cancer detection rates of clinically significant prostate cancer had statistically significant differences: 5.3% in prostate health index <25.0, 7.4% in prostate health index 25.0-34.9, 17.9% in prostate health index 35.0-54.9, and 52.6% in prostate health index ≥55.0 (P < 0.01). Among the patients, 26.9% could have avoided a biopsy with a prostate health index <25.0, at the expense of a 5.3% risk of missing clinically significant prostate cancer. Prostate health index could be used as an additional risk stratification tool for patients with Prostate Imaging Reporting and Data System score 3 lesions. Biopsies could be avoided in patients with low prostate health index, with a small risk of missing clinically significant prostate cancer.
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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.
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Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Hiperplasia Prostática/genética , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Risco , Medição de RiscoRESUMO
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.
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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.
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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.
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Neoplasias da Próstata , Conduta Expectante , Masculino , Adulto , Humanos , Conduta Expectante/métodos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/terapia , Próstata , Fatores Socioeconômicos , Fatores de RiscoRESUMO
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.
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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.
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Próstata , Neoplasias da Próstata , Humanos , Masculino , Biópsia , População do Leste Asiático , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos Prospectivos , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Medição de Risco/métodos , Fatores de RiscoRESUMO
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.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Ubiquitina-Proteína Ligases , Humanos , Masculino , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , ATPases Associadas a Diversas Atividades Celulares/uso terapêutico , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Sistemas CRISPR-Cas , Detecção Precoce de Câncer , Ensaios de Triagem em Larga Escala , Gradação de Tumores , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Proteômica , Ubiquitina-Proteína Ligases/genética , Ubiquitinas/genética , Ubiquitinas/metabolismo , Ubiquitinas/uso terapêuticoRESUMO
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.