Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 16.827
Filtrar
1.
Methods Mol Biol ; 2292: 49-56, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33651351

RESUMEN

Urine cell-free DNA has been shown as an informative noninvasive source of biomarkers for a number of diseases, especially for urological cancers. Starting from the hypothesis that the gain of c-Myc gene is a frequent aberration in several cancer types, including prostate cancer, we analyzed c-Myc copy number variation in urine, studying a little case series of prostate cancer patients, to test its feasibility. Here we report a general protocol that may be considered to analyze gene copy number variation in the urine cell-free fraction.


Asunto(s)
Ácidos Nucleicos Libres de Células/genética , Variaciones en el Número de Copia de ADN , Genes myc , Neoplasias de la Próstata/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/orina , Ácidos Nucleicos Libres de Células/orina , Humanos , Masculino , Neoplasias de la Próstata/orina
2.
Methods Mol Biol ; 2292: 73-94, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33651353

RESUMEN

The characterization of circulating tumor cells (CTCs) is now widely studied as a promising source of cancer-derived biomarkers because of their role in tumor formation and progression. However, CTCs analysis presents some limitations and no standardized method for CTCs isolation from urine has been defined so far. In fact, besides blood, urine represents an ideal source of noninvasive biomarkers, especially for the early detection of genitourinary tumors. Besides CTCs, long noncoding RNAs (lncRNAs) have also been proposed as potential noninvasive biomarkers, and the evaluation of the diagnostic accuracy of urinary lncRNAs has dramatically increased over the last years, with many studies being published. Therefore, this review provides an update on the clinical utility of urinary lncRNAs as novel biomarkers for the diagnosis of bladder and prostate cancers.


Asunto(s)
Neoplasias de la Próstata/orina , ARN Largo no Codificante/orina , Neoplasias de la Vejiga Urinaria/orina , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/orina , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genética
3.
Nat Commun ; 12(1): 1426, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658518

RESUMEN

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Antígenos B7/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Masculino , Adhesión en Parafina , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Análisis de Matrices Tisulares , Transcriptoma
4.
Nat Commun ; 12(1): 1946, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782401

RESUMEN

Numerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Ribonucleoproteína Nuclear Heterogénea A1/genética , Neoplasias de la Próstata/genética , Proteína-Arginina N-Metiltransferasas/genética , Empalme Alternativo , Secuencia de Aminoácidos , Arginina/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Inhibidores Enzimáticos/farmacología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Ribonucleoproteína Nuclear Heterogénea A1/antagonistas & inhibidores , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Humanos , Masculino , Metilación/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Empalmosomas/efectos de los fármacos , Empalmosomas/genética , Empalmosomas/metabolismo , Especificidad por Sustrato
5.
Nat Commun ; 12(1): 1781, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741908

RESUMEN

Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.


Asunto(s)
Sistemas CRISPR-Cas , Metilación de ADN , Edición Génica/métodos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Neoplasias de la Próstata/genética , Animales , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Sitios de Carácter Cuantitativo/genética , Elementos Reguladores de la Transcripción/genética , Factores de Riesgo
6.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Nat Commun ; 12(1): 1812, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753739

RESUMEN

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.


Asunto(s)
Carcinogénesis/metabolismo , Hexoquinasa/metabolismo , Mitocondrias/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Docetaxel/farmacología , Hexoquinasa/genética , Humanos , Masculino , Ratones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Unión Proteica , Sumoilación , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
8.
Nat Commun ; 12(1): 1236, 2021 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-33623038

RESUMEN

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.


Asunto(s)
Grupos Étnicos/genética , Herencia Multifactorial/genética , Neoplasias de la Próstata/genética , Anciano , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Autoinforme
9.
Nat Commun ; 12(1): 734, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531470

RESUMEN

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.


Asunto(s)
Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Represoras/metabolismo , Regulador Transcripcional ERG/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Humanos , Inmunohistoquímica , Inmunoprecipitación , Masculino , Ratones , Ratones Desnudos , Mutación/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Neoplasias de la Próstata/genética , Unión Proteica , Proteómica , Receptores Androgénicos/metabolismo , Proteínas Represoras/genética , Transducción de Señal/fisiología , Regulador Transcripcional ERG/genética , Complejos de Ubiquitina-Proteína Ligasa/genética
10.
Medicine (Baltimore) ; 100(4): e23816, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530178

RESUMEN

ABSTRACT: The evidence for associations between family history of prostate cancer and the risk of breast cancer and ovarian cancer is inconclusive. The first systematic review and meta-analysis of studies was conducted to assess the risk of breast cancer and ovarian cancer associated with a family history of prostate cancer.A literature search was conducted using MEDLINE, Embase and Web of science databases up to January 31, 2019. Data were screened and extracted independently by 2 reviewers. The pooled risk ratio (RR) and its 95% confidence interval (CI) were calculated using random-effects models. The GRADE approach was used to assess the quality of evidence.Nine observational studies including 8,011,625 individuals were included in the meta-analysis. The meta-analysis showed that family history of prostate cancer in first-degree relatives was associated with an increased risk of breast cancer (RR 1.12, 95%CI 1.09 to 1.14) with moderate quality evidence, subgroup analysis showed consistent results. Compared with no family history of prostate cancer, history of prostate cancer in first-degree relatives was associated with a slight risk of ovarian cancer (1.10, 95%CI 1.01 to 1.20) with moderate quality evidence. Family history of prostate cancer among sibling was associated with a 17% increased risk of ovarian cancer (95% CI 1.03 to 1.34), however, no significant association was found between family history of prostate cancer among parent and risk of ovarian cancer (RR 1.19, 95% CI 0.84 to 1.70).This review demonstrates that women with a family history of prostate cancer in first-degree relatives was associated with an increased risk of breast cancer and ovarian cancer. These findings may aid in screening, earlier detection and treatment of women with a family history of prostate cancer in first-degree relatives.


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Neoplasias de la Próstata/genética , Femenino , Humanos , Masculino , Anamnesis , Factores de Riesgo
12.
Nat Commun ; 12(1): 1117, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602919

RESUMEN

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.


Asunto(s)
Modelos Biológicos , Organoides/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Andrógenos/metabolismo , Antineoplásicos/uso terapéutico , Genoma Humano , Humanos , Masculino , Mutación/genética , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Transcriptoma/genética
13.
BMJ ; 372: n214, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589468

RESUMEN

OBJECTIVE: To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. DESIGN: Retrospective, population based diagnostic evaluation. PARTICIPANTS: 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. MAIN OUTCOME MEASURES: Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. RESULTS: Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). CONCLUSIONS: SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Neoplasias de la Mama/genética , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas/métodos , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/genética , Sistema de Registros , Estudios Retrospectivos , Análisis de Secuencia de ADN
14.
Nat Commun ; 12(1): 935, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568675

RESUMEN

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.


Asunto(s)
Células Plasmáticas/inmunología , Neoplasias de la Próstata/inmunología , Afroamericanos/genética , Anciano , Movimiento Celular , Estudios de Cohortes , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Próstata/inmunología , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología
15.
Nat Genet ; 53(1): 65-75, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33398198

RESUMEN

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Asunto(s)
Grupos de Población Continentales/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata/genética , Humanos , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Invasividad Neoplásica , Oportunidad Relativa , Neoplasias de la Próstata/diagnóstico , Factores de Riesgo
16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(2): 113-118, 2021 Feb.
Artículo en Chino | MEDLINE | ID: mdl-33504416

RESUMEN

Objective To investigate the clinical significance of immune-related long non-coding RNAs (lncRNAs) and their potential role in guiding the treatment of prostate cancer. Methods lncRNAs of prostate cancer were obtained from TCGA database. The immune-related gene sets were downloaded from Molecular Signatures Database. Gene-lncRNA co-expression was confirmed by Pearson correlation analysis, and univariate Cox regression and selected operator regression (Lasso) were performed to identify important and immune-related lncRNAs. "gglot package" and "survival package" of R software were used to evaluate the correlation between the lncRNAs and clinical characteristics and the prognostic value of the lncRNAs. lnc2RNA database was used to analyze the difference of lncRNAs between normal prostate tissue and prostate cancer tissue. Starbase and David database were used to determine the predict function of lncRNAs in prostate cancer. Results AL162586.1, AC138028.4, SLC25A25-AS1, AC002553.1, AC004816.1, LINC00641 and AC027796.4 were key immune-related lncRNAs, and their expression was positively associated with N stage; the expression levels of AL162586.1 and SLC25A25-AS1 increased with higher T stage. The expression levels of SLC25A25-AS1 and LINC00641 were significantly different in tumor tissues from that of normal tissues. The GO enrichment showed that SLC25A25-AS1 was mainly distributed in membrane, had negative regulation of mRNA splicing via spliceosome and by a nucleotide binding. KEGG pathway enrichment showed that targeted genes were mainly involved in spliceosome pathway. Conclusion lncRNA has become a new research direction in prostate cancer and SLC25A25-AS1 may affect the prognosis of patients through splicing pathway.


Asunto(s)
Neoplasias de la Próstata , ARN Largo no Codificante , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Pronóstico , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética
17.
APMIS ; 129(4): 204-212, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33455017

RESUMEN

The aim of this study was to validate prostate cancer-associated genes on transcript level and to assess the prognostic value of the most promising markers by immunohistochemistry. Based on differentially expressed genes found in a previous study, 84 genes were further validated using mRNA expression data and follow-up information from the Cancer Genome Atlas (TCGA) prostate cancer cohort (n = 497). Immunohistochemistry was used for validation of three genes in an independent, clinically annotated prostatectomy patient cohort (n = 175) with biochemical relapse as endpoint. Also, associations with clinicopathological variables were evaluated. Eleven protein-coding genes from the list of 84 genes were associated with biochemical recurrence-free survival on mRNA expression level in multivariate Cox-analyses. Three of these genes (TSPAN1, ESRP1 and KIAA1324) were immunohistochemically validated using an independent cohort of prostatectomy patients. Both ESRP1 and KIAA1324 were independently associated with biochemical recurrence-free survival. TSPAN1 was univariately prognostic but failed significance on multivariate analysis, probably due to its strong correlation with high Gleason scores. Multistep filtering using the publicly available TCGA cohort, data of an earlier expression profiling study which profiled 3023 cancer-associated transcripts in 42 primary prostate cancer cases, identified two novel candidate prognostic markers (ESRP1 and KIAA1324) of primary prostate cancer for further study.


Asunto(s)
Biomarcadores de Tumor/genética , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Proteínas de Unión al ARN/genética , Tetraspaninas/genética , Anciano , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/patología
18.
Gene ; 774: 145432, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33444688

RESUMEN

Previous studies have found the relationship between cholesterol biosynthesis pathway genes and the risk or prognosis of prostate cancer (PCa), while there is no definite evidence that genetic variants in the cholesterol biosynthesis pathway gene is related to PCa risk. Consequently, we performed this study to explore the associations of single-nucleotide polymorphisms (SNPs) in the cholesterol biosynthesis pathway with PCa risk. We systematically evaluated the association of SNPs in 21 cholesterol biosynthesis pathway genes with the risk of PCa using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial database using a logistic regression model. Gene expression data of PCa from Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database were applied for mRNA expression analysis. The TCGA database was used to perform expression quantitative trait loci (eQTL) analysis. The interaction between demographic factors and SNPs was analyzed using two-by-four tables. We found T allele of rs67415672 in HMGCS1 is a significant protective allele of PCa [adjusted odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.83-0.97, P = 4.16 × 10-3]. Moreover, rs67415672 was an eQTL for HMGCS1 (P = 2.23 × 10-6). The expression of HMGCS1 significantly decreased in PCa primary tumors than that in normal tissues. These findings indicated that the HMGCS1 rs67415672 might be possible functional susceptibility loci for PCa.


Asunto(s)
Colesterol/genética , Neoplasias de la Próstata/genética , Anciano , Colesterol/biosíntesis , Simulación por Computador , Bases de Datos Genéticas , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Sitios de Carácter Cuantitativo
19.
Environ Pollut ; 272: 116397, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33433340

RESUMEN

Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and ß-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and ß-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.


Asunto(s)
Andrógenos , Neoplasias de la Próstata , Antagonistas de Andrógenos , Línea Celular Tumoral , Proliferación Celular , Epigénesis Genética , Humanos , Masculino , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo
20.
Int J Nanomedicine ; 16: 315-327, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33469288

RESUMEN

Background: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined. Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression. Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation. Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.


Asunto(s)
Andrógenos/farmacología , Exosomas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Neoplasias de la Próstata/patología , Regulación hacia Arriba/efectos de los fármacos , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Exosomas/ultraestructura , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Microambiente Tumoral
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...