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1.
Nat Cell Biol ; 23(4): 341-354, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33795875

RESUMO

Dysregulated translation is a common feature of cancer. Uncovering its governing factors and underlying mechanism are important for cancer therapy. Here, we report that enhancer of zeste homologue 2 (EZH2), previously known as a transcription repressor and lysine methyltransferase, can directly interact with fibrillarin (FBL) to exert its role in translational regulation. We demonstrate that EZH2 enhances rRNA 2'-O methylation via its direct interaction with FBL. Mechanistically, EZH2 strengthens the FBL-NOP56 interaction and facilitates the assembly of box C/D small nucleolar ribonucleoprotein. Strikingly, EZH2 deficiency impairs the translation process globally and reduces internal ribosome entry site (IRES)-dependent translation initiation in cancer cells. Our findings reveal a previously unrecognized role of EZH2 in cancer-related translational regulation.

2.
Lancet Oncol ; 22(3): 402-410, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33662287

RESUMO

BACKGROUND: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. METHODS: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. FINDINGS: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. INTERPRETATION: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. FUNDING: Prostate Cancer Foundation and National Institutes of Health.


Assuntos
Biomarcadores/análise , Recidiva Local de Neoplasia/mortalidade , Neoplasias da Próstata/mortalidade , Idoso , Terapia Combinada , Seguimentos , Humanos , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Taxa de Sobrevida
4.
Nat Commun ; 12(1): 935, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568675

RESUMO

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.


Assuntos
Plasmócitos/imunologia , Neoplasias da Próstata/imunologia , Afro-Americanos/genética , Idoso , Movimento Celular , Estudos de Coortes , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Próstata/imunologia , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia
5.
J Urol ; : 101097JU0000000000001670, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33625901
6.
Mod Pathol ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462368

RESUMO

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p < 0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.

7.
J Urol ; 205(4): 1206, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33464930
8.
Urology ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33482136

RESUMO

OBJECTIVE: To determine whether the academic achievement of Department Chairperson (DC) and Research Director (RD), when present, is associated with increased scholarly productivity and National Institutes of Health (NIH) funding of faculty members in academic urology departments. MATERIALS AND METHODS: We identified the DC, RD and faculty members of 145 academic urology departments. The scholarly productivity and NIH funding for each individual faculty member was assessed from 2018 to 2019 using an h-index extrapolated from the Scopus database and the NIH RePORTER tool, respectively. The Spearman correlation coefficient was employed to define the correlation of these parameters. Hypothesis testing was conducted using the Mann-Whitney U test. RESULTS: After excluding 13 departments due to missing faculty listing, our final sample included 132 departments and 2227 faculty members. In 2018, the NIH provided $55,243,658 in urology research grants to 24.2% of departments and 4.0% of faculty members. Of departments with NIH funding, 68.8% employed a RD. DC and RD h-index were positively correlated with departmental h-index. DC h-index positively correlated with department NIH funding. Moreover, NIH funding was significantly higher for departments with a RD vs those without a RD ($1,268,028 vs $62,941, P < .001); interestingly, NIH funding was higher for departments employing unfunded RDs vs those without a RD ($2,079,948 vs $579,055, P < .001). CONCLUSION: Academic success of a DC and RD was associated with urology departmental scholarly productivity and NIH funding. The presence of a RD, funded or unfunded, was associated with increased departmental NIH funding.

10.
J Urol ; 205(3): 910-911, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33369506
11.
Eur Urol ; 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33293078

RESUMO

CONTEXT: Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use. OBJECTIVE: To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC). EVIDENCE ACQUISITION: The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446-52) and American Urology Association (AUA) criteria. EVIDENCE SYNTHESIS: In total, 42 studies and 30407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n=12141), prospective registries (n=17053), and prospective and post hoc randomized trial analyses (n=1213). In 32 studies (n=12600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n=8543). GC use changed the management in active surveillance (number needed to test [NNT]=9) and postprostatectomy (NNT=1.5-4) settings in five studies (n=4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state. CONCLUSIONS: Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making. PATIENT SUMMARY: In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.

12.
J Urol ; : 101097JU0000000000001498, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33200641
13.
Prostate ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33141952

RESUMO

BACKGROUND: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERGnegative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied. METHODS: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections. RESULTS: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERGnegative 81.4% vs. ERGpositive 18.6%; p = .005) and EAM (ERGnegative 60.4% vs. ERGpositive 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERGnegative (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERGnegative were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC). CONCLUSIONS: ERGnegative tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.

14.
J Urol ; : 101097JU0000000000001453, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33103942

RESUMO

PURPOSE: Prostate Health Index (PHI) is validated for prostate cancer (PCa) detection but has not been well validated for Gleason grade group (GG) 2-5 PCa detection in Black men. We hypothesize that PHI has greater accuracy than PSA for detection of GG2-5 PCa. We estimated probability of overall and GG2-5 PCa across previously established PHI ranges and identified PHI cutoffs that maximize specificity for GG2-5 PCa with sensitivity >90%. MATERIALS AND METHODS: We recruited a 'cancer-free' Black control cohort (n=135) and a cohort of biopsy-naïve Black men (n=158) biopsied for elevated PSA. Descriptive statistics compared the PCa cases and controls and the frequency of GG2-5 PCa across PHI scores. Receiver operating characteristics compared the discrimination of PSA, PHI, and other PSA-related biomarkers. Sensitivity and specificity for GG2-5 PCa detection were assessed at PSA and PHI thresholds alone and in series. RESULTS: Of biopsied subjects, 32.9% had GG2-5 PCa. In Blacks with PSA from 4.0-10.0 ng/mL, PHI and PSA had similar discrimination for GG2-5 PCa (0.63 vs. 0.57, p=0.27). In Blacks with PSA ≤10.0, a threshold of PSA ≥4.0 had 90.4% sensitivity for GG2-5 PCa; a threshold of PSA ≥4.0 with PHI ≥35.0 in series avoided unnecessary biopsy in 33.0% of men but missed 17.3% of GG2-5 PCa. PSA ≥4.0 with PHI ≥28.0 in series spared biopsy in 17.9%, while maintaining 90.4% sensitivity of GG2-5 PCa. CONCLUSIONS: PHI has moderate accuracy in detecting GG2-5 PCa in Blacks, but PHI ≥28.0 can be safely used to avoid some unnecessary biopsies in Blacks.

19.
Prostate ; 80(12): 1012-1023, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649013

RESUMO

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.


Assuntos
Células Neuroendócrinas/patologia , Tumores Neuroendócrinos/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Diferenciação Celular/fisiologia , Estudos de Coortes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Células Neuroendócrinas/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
J Clin Med ; 9(6)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599760

RESUMO

BACKGROUND: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. METHODS: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n = 492) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox regression multivariable analyses. RESULTS: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), and M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Mid, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3 and 4) demonstrated worse PFS (HR 2.24, 95% CI 1.46-3.45, p = 0.0002) than the clusters 1 and 2. No metastatic events occurred in the plasma cell enriched, non-macrophage-enriched clusters. Comparing clusters 3 vs. 4, in patients treated by surgery alone, cluster 3 had zero progression events (p < 0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p = 0.018). CONCLUSION: Distinct tumor immune clusters with a macrophage-enriched, plasma cell non-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

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