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1.
J Natl Cancer Inst ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853339

RESUMO

BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease. METHODS: Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

2.
Eur Urol ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32800727

RESUMO

BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

3.
Int J Cancer ; 147(10): 2735-2742, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32399975

RESUMO

Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218 084 men in the population-based UK Biobank cohort, aged 40 to 69 at study entry between 2006 and 2010, with follow-up through mid-2015. We assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of PC and previous prostate-specific antigen testing. Mean age at study entry was 56 years, 94% of the men were white, and 1.1% (n = 2311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.03-1.67, P = .029). The association with PC was only among men with the ulcerative colitis (UC; aHR = 1.47, 95% CI = 1.11-1.95, P = .0070), and not Crohn's disease (aHR 1.06, 95% CI = 0.63-1.80, P = .82). Results are limited by lack of data on frequency of health care interactions. In a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis.

4.
Prostate ; 80(4): 352-364, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31905248

RESUMO

BACKGROUND: Signal regulatory protein ß1 (SIRPB1) is a signal regulatory protein member of the immunoglobulin superfamily and is capable of modulating receptor tyrosine kinase-coupled signaling. Copy number variations at the SIRPB1 locus were previously reported to associate with prostate cancer aggressiveness in patients, however, the role of SIRPB1 in prostate carcinogenesis is unknown. METHODS: Fluorescence in situ hybridization and laser-capture microdissection coupled with quantitative polymerase chain reaction was utilized to determine SIRPB1 gene amplification and messenger RNA expression in prostate cancer specimens. The effect of knockdown of SIRPB1 by RNA interference in PC3 prostate cancer cells on cell growth in colony formation assays and cell mobility in wound-healing, transwell assays, and cell cycle analysis was determined. Overexpression of SIPRB1 in C4-2 prostate cancer cells on cell migration, invasion, colony formation and cell cycle progression and tumor take rate in xenografts was also determined. Western blot assay of potential downstream SIRPB1 pathways was also performed. RESULTS: SIRPB1 gene amplification was detected in up to 37.5% of prostate cancer specimens based on in silico analysis of several publicly available datasets. SIRPB1 gene amplification and overexpression were detected in prostate cancer specimens. The knockdown of SIRPB1 significantly suppressed cell growth in colony formation assays and cell mobility. SIRPB1 knockdown also induced cell cycle arrest during the G0 /G1 phase and enhancement of apoptosis. Conversely, overexpression of SIPRB1 in C4-2 prostate cancer cells significantly enhanced cell migration, invasion, colony formation, and cell cycle progression and increased C4-2 xenograft tumor take rate in nude mice. Finally, this study presented evidence for SIRPB1 regulation of Akt phosphorylation and showed that Akt inhibition could abolish SIRPB1 stimulation of prostate cancer cell proliferation. CONCLUSIONS: These results suggest that SIRPB1 is a potential oncogene capable of activating Akt signaling to stimulate prostate cancer proliferation and could be a biomarker for patients at risk of developing aggressive prostate cancer.


Assuntos
Moléculas de Adesão de Célula Nervosa/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Ativação Enzimática , Amplificação de Genes , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Moléculas de Adesão de Célula Nervosa/biossíntese , Células PC-3 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais
5.
Cell Death Dis ; 10(11): 801, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641103

RESUMO

The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell death in both hormone sensitive and castration-resistant prostate cancer cells. EPHB4 inhibition reduced expression of the glucose transporter, GLUT3, impaired glucose uptake, and reduced cellular ATP levels. This was associated with the activation of endoplasmic reticulum stress and tumor cell death with features of immunogenic cell death (ICD), including phosphorylation of eIF2α, increased cell surface calreticulin levels, and release of HMGB1 and ATP. The changes in tumor cell metabolism after EPHB4 inhibition were associated with MYC downregulation, likely mediated by the SRC/p38 MAPK/4EBP1 signaling cascade, known to impair cap-dependent translation. Together, our study indicates a role for EPHB4 inhibition in the induction of immunogenic cell death with implication for prostate cancer therapy.


Assuntos
Estresse do Retículo Endoplasmático/imunologia , Morte Celular Imunogênica/imunologia , Neoplasias da Próstata/imunologia , Receptor EphB4/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptor EphB4/genética , Receptor EphB4/imunologia , Receptor EphB4/metabolismo , Transdução de Sinais
6.
Urology ; 129: 153-159, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30926382

RESUMO

OBJECTIVE: To evaluate prognostic markers, prostate-specific antigen, prostate health index (PHI), and prostate volume indexed measures (prostate-specific antigen density and prostate health index density) for predicting positive prostate cancer biopsies in magnetic resonance (MR) transrectal ultrasound fused versus nonfused transrectal ultrasonography biopsy. METHODS: A retrospective cohort of 211 patients that had at least 1 suspected MR lesion, Prostate Imaging-Reporting and Data System ≥3, and subsequent biopsy (2015-2017). Clinical characteristics and prognostic biomarkers were evaluated as predictors of prostate cancer detection by type of biopsy guidance (fused vs nonfused). RESULTS: One-hundred twenty-one patients had nonfused and 90 had fused biopsies. PHI and PHID had greater area under the receiver operating characteristics curve (AUC) in predicting positive biopsies than prostate-specific antigen or PSAD for both nonfused and fused biopsy. PHI 0.78 (95% CI 0.67-0.88) and PHID 0.82 (95% CI 0.73-0.91) had the greatest AUC for predicting biopsy results for nonfused and fused biopsies, respectively. Multiple-variable models did not improve model fit compared to single variables. Based on Youden's index, a cut-off value of 45.9 for PHI in nonfused and 0.64 for PHID in fused biopsies would reduce the number of negative biopsies by 77.3% and 63.4%, respectively, but the percentage of missed clinically significant cancer biopsies would be 19% and 12%, respectively. CONCLUSION: Our findings demonstrate that the choice of prognostic biomarkers for predicting positive biopsies is a function of the biopsy guidance method. Volume indexed derivatives appear to have greater value when a MRI-US fused method is used.


Assuntos
Endossonografia/métodos , Biópsia Guiada por Imagem/métodos , Imagem por Ressonância Magnética/métodos , Estadiamento de Neoplasias/métodos , Antígeno Prostático Específico/sangue , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico , Idoso , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Reto , Estudos Retrospectivos
7.
PLoS One ; 14(3): e0214078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30917169

RESUMO

BACKGROUND: Long term dietary consumption of genistein by Chinese men is associated with decreased PCa metastasis and mortality. Short term treatment of US men with prostate cancer (PCa) with genistein decreases MMP-2 in prostate tissue. MEK4 regulates MMP-2 expression, drives PCa metastasis, and genistein inhibits MEK4, decreases MMP-2 expression and dietary dosing inhibits human PCa metastasis in mice. This study examines short- versus long-term treatment effects of genistein in humans and in vitro. METHODS AND FINDINGS: US men with localized PCa were treated on a phase II trial with genistein (N = 14) versus not (N = 14) for one month prior to radical prostatectomy. Prostate epithelial cells were removed from fresh frozen tissue by laser capture microdissection, and the expression of 12,000 genes profiled. Genistein significantly altered the expression of four genes, three had established links to cancer cell motility and metastasis. Of these three, one was a non-coding transcript, and the other two were BASP1 and HCF2. Genistein increased BASP1 expression in humans, and its engineered over expression and knockdown demonstrated that it suppressed cell invasion in all six human prostate cell lines examined. Genistein decreased HCF2 expression in humans, and it was shown to increase cell invasion in all cell lines examined. The expression of MMP-2, MEK4 and BASP1 was then measured in formalin fixed prostate tissue from N = 38 Chinese men living in China and N = 41 US men living in the US, both cohorts with localized PCa. MMP-2 was 52% higher in Chinese compared to US tissue (P < 0.0001), MEK4 was 48% lower (P < 0.0001), and BASP1 was unaltered. Treatment of PC3 human PCa cells in vitro for up to 8 weeks demonstrated that short term genistein treatment decreased MMP-2, while long term treatment increased it, both changes being significant (P<0.05) compared to untreated control cells. Long term genistein-treated cells retained their responsiveness to genistein's anti-motility effect. CONCLUSIONS: Genistein inhibits pathways in human prostate that drive transformation to a lethal high motility phenotype. Long term treatment induces compensatory changes in biomarkers of efficacy. The current strategy of using such biomarkers after short term intervention as go/no-go determinants in early phase chemoprevention trials should be carefully examined.


Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular/efeitos dos fármacos , Genisteína/administração & dosagem , Proteínas de Neoplasias/metabolismo , Próstata , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Metástase Neoplásica , Células PC-3 , Próstata/metabolismo , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
8.
Prostate Cancer Prostatic Dis ; 22(3): 362-381, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30655600

RESUMO

BACKGROUND: Prostate cancer is the most common cancer in American men that ranges from low risk states amenable to active surveillance to high-risk states that can be lethal especially if untreated. There is a critical need to develop relatively non-invasive and clinically useful methods for screening, detection, prognosis, disease monitoring, and prediction of treatment efficacy. In this review, we focus on important advances as well as future efforts needed to drive clinical innovation in this area of urine biomarker research for prostate cancer detection and prognostication. METHODS: We provide a review of current literature on urinary biomarkers for prostate cancer. We evaluate the strengths and limitations of a variety of approaches that vary in sampling strategies and targets measured; discuss reported urine tests for prostate cancer with respect to their technical, analytical, and clinical parameters; and provide our perspectives on critical considerations in approaches to developing a urine-based test for prostate cancer. RESULTS: There has been an extensive history of exploring urine as a source of biomarkers for prostate cancer that has resulted in a variety of urine tests that are in current clinical use. Importantly, at least three tests have demonstrated high sensitivity (~90%) and negative predictive value (~95%) for clinically significant tumors; however, there has not been widespread adoption of these tests. CONCLUSIONS: Conceptual and methodological advances in the field will help to drive the development of novel urinary tests that in turn may lead to a shift in the clinical paradigm for prostate cancer diagnosis and management.


Assuntos
Biomarcadores Tumorais/urina , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Próstata/diagnóstico , Progressão da Doença , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Próstata/patologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Neoplasias da Próstata/urina
9.
Eur Urol ; 75(5): 846-852, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30528221

RESUMO

BACKGROUND: There are limited data examining the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD). OBJECTIVE: To compare the incidence of PCa between men with and those without IBD. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, matched-cohort study involving a single academic medical center and conducted from 1996 to 2017. Male patients with IBD (cases=1033) were randomly matched 1:9 by age and race to men without IBD (controls=9306). All patients had undergone at least one prostate-specific antigen (PSA) screening test. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier and multivariable Cox proportional hazard models, stratified by age and race, evaluated the relationship between IBD and the incidence of any PCa and clinically significant PCa (Gleason grade group ≥2). A mixed-effect regression model assessed the association of IBD with PSA level. RESULTS AND LIMITATIONS: PCa incidence at 10yr was 4.4% among men with IBD and 0.65% among controls (hazard ratio [HR] 4.84 [3.34-7.02] [3.19-6.69], p<0.001). Clinically significant PCa incidence at 10yr was 2.4% for men with IBD and 0.42% for controls (HR 4.04 [2.52-6.48], p<0.001). After approximately age 60, PSA values were higher among patients with IBD (fixed-effect interaction of age and patient group: p=0.004). Results are limited by the retrospective nature of the analysis and lack of external validity. CONCLUSIONS: Men with IBD had higher rates of clinically significant PCa when compared with age- and race-matched controls. PATIENT SUMMARY: This study of over 10000 men treated at a large medical center suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population.


Assuntos
Doenças Inflamatórias Intestinais/epidemiologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Adulto , Idoso , Estudos de Casos e Controles , Humanos , Incidência , Doenças Inflamatórias Intestinais/sangue , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/sangue , Estudos Retrospectivos , Fatores de Risco
10.
Urol Oncol ; 36(11): 501.e1-501.e8, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30236853

RESUMO

INTRODUCTION AND OBJECTIVE: Studies have linked Black race to prostate cancer (CaP) risk but most fail to account for established risk factors such as 5-ARI use, prostate volume, socioeconomic status, and hospital setting. We assess whether Black race remains associated with CaP and Gleason ≥3 + 4 CaP, after adjusting for clinical setting and socioeconomic and clinical factors at prostate biopsy, with a focus on men aged 40-54 years, who may be excluded from current screening guidelines. METHODS: We recruited 564 men age 40-79 undergoing initial prostate biopsy for abnormal PSA or digital rectal examination (DRE) from three publicly funded and two private hospitals from 2009-2014. Univariate and multivariate analyses examined the associations between hospital type, race, West African Ancestry (WAA), clinical, and sociodemographic risk factors with CaP diagnosis and Gleason ≥3 + 4 CaP. Given changes in CaP screening recommendations, we also assess the multivariate analyses for men aged 40-54. RESULTS: Black and White men had similar age, BMI, and prostate volume. Black men had higher PSA (8.10 ng/mL vs. 5.63 ng/mL) and PSA density (0.22 ng/mL/cm3 vs. 0.15 ng/mL/cm3, all p < 0.001). Blacks had higher frequency of CaP (63.1% vs. 41.5%, p<0.001) and Gleason ≥3+4 CaP relative to Whites in both public (27.7% vs 11.6%, p<0.001) and private (48.4% vs 21.6%, p = 0.002) settings. In models adjusted for age, first degree family history, prostate volume, 5-ARI use, hospital type, income, marital and educational status, Black race was independently associated with overall CaP diagnosis (OR = 2.13, p = 0.002). There was a significant multiplicative interaction with Black race and abnormal DRE for Gleason ≥3 + 4 CaP (OR = 2.93, p = 0.01). WAA was not predictive of overall or significant CaP among Black men. Black race (OR = 5.66, p = 0.02) and family history (OR = 4.98, p = 0.01) were independently positively associated with overall CaP diagnosis for men aged 40 to 54. CONCLUSIONS: Black race is independently associated with CaP and Gleason ≥3+4 CaP after accounting for clinical and socioeconomic risk factors including clinical setting and WAA, and has a higher odds ratio of CaP diagnosis in younger men. Further investigation into optimizing screening in Black men aged 40 to 54 is warranted.


Assuntos
Afro-Americanos/estatística & dados numéricos , Neoplasias da Próstata/etnologia , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Autorrelato , Fatores Socioeconômicos
11.
J Urol ; 200(5): 1048-1055, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29852180

RESUMO

PURPOSE: Shared decision making is recommended in regard to prostate cancer screening. Decision aids may facilitate this process but the impact of decision aids on screening preferences is poorly understood. MATERIALS AND METHODS: In an online survey we randomized a national sample of adults to the online decision aids of 1 of 6 professional societies. We compared survey responses before and after decision aid exposure. The primary outcome was the change in participant likelihood of undergoing or recommending prostate cancer screening on a scale of 1-unlikely to 100-extremely likely. Secondary outcomes included change in participant comfort with prostate cancer screening based on the average of 6, 5-point Likert-scale questions. RESULTS: Median age was 53 years in the 1,336 participants and 50% were men. The randomized groups did not differ significantly by race, age, gender, income, marital status or education level. The likelihood of undergoing or recommending prostate cancer screening decreased from 83 to 78 following decision aid exposure (p <0.001). Reviewing the decision aid from the Centers for Disease Control or the American Academy of Family Physicians did not alter the likelihood (each p >0.2). However, the decision aid from the United States Preventive Services Task Force was associated with the largest decrease in screening preference (-16.0, p <0.001). Participants reported increased comfort (from 3.5 to 4.1 of 5) with the decision making process of prostate cancer screening following exposure to a decision aid (p <0.001). CONCLUSIONS: Exposure to a decision aid decreased the participant likelihood of undergoing or recommending prostate cancer screening and increased comfort with the screening process.


Assuntos
Tomada de Decisão Clínica/métodos , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Neoplasias da Próstata/diagnóstico , Idoso , Tomada de Decisões , Detecção Precoce de Câncer/efeitos adversos , Detecção Precoce de Câncer/psicologia , Feminino , Humanos , Internet , Masculino , Programas de Rastreamento/psicologia , Pessoa de Meia-Idade , Conforto do Paciente/estatística & dados numéricos , Educação de Pacientes como Assunto , Participação do Paciente , Preferência do Paciente/psicologia , Preferência do Paciente/estatística & dados numéricos , Distribuição Aleatória , Inquéritos e Questionários/estatística & dados numéricos , Estados Unidos
12.
Med Clin North Am ; 102(2): 199-214, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29406053

RESUMO

During the prostate-specific antigen-based prostate cancer (PCa) screening era there has been a 53% decrease in the US PCa mortality rate. Concerns about overdiagnosis and overtreatment combined with misinterpretation of clinical trial data led to a recommendation against PCa screening, resulting in a subsequent reversion to more high-risk disease at diagnosis. Re-evaluation of trial data and increasing acceptance of active surveillance led to a new draft recommendation for shared decision making for men aged 55 to 69 years old. Further consideration is needed for more intensive screening in men with high-risk factors. PCa screening significantly reduces PCa morbidity and mortality.


Assuntos
Detecção Precoce de Câncer , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Biomarcadores Tumorais/sangue , Tomada de Decisões , Detecção Precoce de Câncer/estatística & dados numéricos , Humanos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Sobremedicalização , Participação do Paciente , Atenção Primária à Saúde , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Estados Unidos/epidemiologia
13.
J Clin Oncol ; 36(4): 414-424, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29236593

RESUMO

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.


Assuntos
Biomarcadores Tumorais/genética , Testes Genéticos/métodos , Neoplasias da Próstata/genética , Adulto , Fatores Etários , Idoso , Tomada de Decisão Clínica , Predisposição Genética para Doença , Testes Genéticos/normas , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Fatores de Risco
14.
Urology ; 110: 267-268, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28847691
15.
Curr Opin Urol ; 27(5): 475-480, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28614085

RESUMO

PURPOSE OF REVIEW: To provide an overview of how genetic, serum, and urine biomarkers can help identify men at high risk for prostate cancer (PCa) and aggressive disease and men who would benefit from prostate biopsy. RECENT FINDINGS: Screening for PCa is controversial because of concerns about overdiagnosis and overtreatment of nonlife-threatening tumors. Therefore, an approach to screening that includes a detailed family history with genetic testing of risk single nucleotide polymorphisms and high-penetrance genetic variants should be considered. After an elevated serum prostate-specific antigen (PSA) level has been confirmed, obtaining additional information (family history, biomarkers, and imaging) should be considered before recommending a prostate biopsy. SUMMARY: There are now genetic tests that can help identify men who would benefit from PSA testing. Additional biomarker and imaging tests should be offered to those men who are confirmed to have elevated PSA values. These new biomarkers and imaging tests can improve the specificity of PSA testing while missing a small percentage of high-grade tumors. The path forward involves a multiparametric risk assessment based on clinical data and these new tests.


Assuntos
Biomarcadores Tumorais , Biópsia/métodos , Detecção Precoce de Câncer , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Detecção Precoce de Câncer/tendências , Testes Genéticos , Humanos , Masculino , Neoplasias da Próstata/sangue , Neoplasias da Próstata/urina
16.
J Clin Oncol ; 35(17): 1898-1904, 2017 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-28346806

RESUMO

Purpose The suitability of younger patients with prostate cancer (PCa) for initial active surveillance (AS) has been questioned on the basis of eventual treatment necessity and concerns of safety; however, the role of age on surveillance outcomes has not been well defined. Patients and Methods We identified men managed with AS at our institution with a minimum follow-up of 6 months. The primary study objective was to examine the association of age with risk of biopsy-based Gleason score upgrade during AS. We also examined the association of age with related end points, including overall biopsy-determined progression, definitive treatment, and pathologic and biochemical outcomes after delayed radical prostatectomy (RP), using descriptive statistics, the Kaplan-Meier method, and multivariable Cox proportional hazards regression. Results A total of 1,433 patients were followed for a median of 49 months; 74% underwent initial biopsy at a referring institution. Median age at diagnosis was 63 years, including 599 patients (42%) ≤ 60 years old and 834 (58%) > 60 years old. The 3- and 5-year biopsy-based Gleason score upgrade-free rates were 73% and 55%, respectively, for men ≤ 60 years old compared with 64% and 48%, respectively, for men older than 60 years ( P < .01). On Cox regression analysis, younger age was independently associated with lower risk of biopsy-based Gleason score upgrade (hazard ratio per 1-year decrease, 0.969 [95% CI, 0.956 to 0.983]; P < .01), and persisted upon restriction to men meeting strict AS inclusion criteria. There was no significant association between younger age and risk of definitive treatment or risk of biochemical recurrence after delayed RP. Conclusion Younger patient age was associated with decreased risk of biopsy-based Gleason score upgrade during AS but not with risk of definitive treatment in the intermediate term. AS represents a strategy to mitigate overtreatment in young patients with low-risk PCa in the early term.


Assuntos
Neoplasias da Próstata/patologia , Fatores Etários , Idoso , Biópsia , Estudos de Coortes , Monitoramento Epidemiológico , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Modelos de Riscos Proporcionais , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Estados Unidos/epidemiologia
17.
Genet Epidemiol ; 41(4): 297-308, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28211093

RESUMO

Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results.


Assuntos
Algoritmos , Estudos de Associação Genética/métodos , Variação Genética , Simulação por Computador , Humanos , Modelos Genéticos , Tamanho da Amostra , Estatísticas não Paramétricas
18.
J Urol ; 197(2S): S200-S207, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28012755

RESUMO

To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandom-E or Tandem-R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 µg./l. or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 µg./l., 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 µg./l. or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings.


Assuntos
Exame Retal Digital , Detecção Precoce de Câncer/métodos , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biópsia , Detecção Precoce de Câncer/normas , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Prospectivos , Próstata/diagnóstico por imagem , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Ultrassonografia
19.
BJU Int ; 120(1): 61-68, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27743489

RESUMO

OBJECTIVE: To examine the use of the Prostate Health Index (PHI) as a continuous variable in multivariable risk assessment for aggressive prostate cancer in a large multicentre US study. MATERIALS AND METHODS: The study population included 728 men, with prostate-specific antigen (PSA) levels of 2-10 ng/mL and a negative digital rectal examination, enrolled in a prospective, multi-site early detection trial. The primary endpoint was aggressive prostate cancer, defined as biopsy Gleason score ≥7. First, we evaluated whether the addition of PHI improves the performance of currently available risk calculators (the Prostate Cancer Prevention Trial [PCPT] and European Randomised Study of Screening for Prostate Cancer [ERSPC] risk calculators). We also designed and internally validated a new PHI-based multivariable predictive model, and created a nomogram. RESULTS: Of 728 men undergoing biopsy, 118 (16.2%) had aggressive prostate cancer. The PHI predicted the risk of aggressive prostate cancer across the spectrum of values. Adding PHI significantly improved the predictive accuracy of the PCPT and ERSPC risk calculators for aggressive disease. A new model was created using age, previous biopsy, prostate volume, PSA and PHI, with an area under the curve of 0.746. The bootstrap-corrected model showed good calibration with observed risk for aggressive prostate cancer and had net benefit on decision-curve analysis. CONCLUSION: Using PHI as part of multivariable risk assessment leads to a significant improvement in the detection of aggressive prostate cancer, potentially reducing harms from unnecessary prostate biopsy and overdiagnosis.


Assuntos
Detecção Precoce de Câncer/métodos , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/patologia , Biópsia por Agulha , Técnicas de Apoio para a Decisão , Exame Retal Digital , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Neoplasias da Próstata/sangue , Medição de Risco
20.
Am J Hum Genet ; 99(4): 877-885, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27666373

RESUMO

The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.


Assuntos
Doença/genética , Mutação de Sentido Incorreto/genética , Software , Área Sob a Curva , Análise Mutacional de DNA , Exoma/genética , Frequência do Gene , Humanos , Curva ROC
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