RESUMEN
Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.
Asunto(s)
Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Serina Endopeptidasas/genética , Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Neoplasias de la Próstata/patología , Sitios de Carácter Cuantitativo/genética , Regulador Transcripcional ERG/genéticaRESUMEN
Amplification of the 9p13.3 chromosomal region occurs in a subset of prostate cancers (PCs); however, the target gene or genes of this amplification have remained unidentified. The aim of this study was to investigate the 9p13.3 amplification in more detail to identify genes that are potentially advantageous for cancer cells. We narrowed down the minimally amplified area and assessed the frequency of the 9p13.3 amplification. Of the clinical samples from untreated PCs that were examined (n = 134), 9.7% showed high-level amplification, and 32.1% showed low-level amplification. Additionally, in clinical samples from castration-resistant PCs (n = 70), high- and low-level amplification was seen in 14.3% and 44.3% of the samples, respectively. We next analyzed the protein-coding genes in this chromosomal region for both their expression in clinical PC samples as well as their potential as growth regulators in PC cells. We found that the 9p13.3 amplification harbors several genes that are able to affect the growth of PC cells when downregulated using siRNA. Of these, UBAP2 was the most prominently upregulated gene in the clinical prostate tumor samples. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Proteínas Portadoras/genética , Cromosomas Humanos Par 9/genética , Amplificación de Genes/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata/genética , Anciano , Animales , Línea Celular Tumoral , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Masculino , Ratones , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Asunto(s)
Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. METHODS: The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. RESULTS: ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. CONCLUSIONS: A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. IMPACT: Interaction of PTEN and ERG pathways warrants further studies.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Fosfohidrolasa PTEN/deficiencia , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Transactivadores/biosíntesis , Estudios de Cohortes , Supervivencia sin Enfermedad , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Metástasis de la Neoplasia , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Adhesión en Parafina , Prostatectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/cirugía , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Regulador Transcripcional ERG , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
PURPOSE: The aim of the study was to examine whether TMPRSS2:ERG fusion or SPINK1 protein expression is associated with hormone responsiveness of prostate cancer and can thus be used as a biomarker. EXPERIMENTAL DESIGN: Diagnostic needle biopsies from prostate cancer patients primarily treated by endocrine therapy were evaluated for TMPRSS2:ERG fusion with fluorescence in situ hybridization and SPINK1 protein expression with immunohistochemistry. RESULTS: The frequency of TMPRSS2:ERG fusion in 178 biopsies of hormonally treated patients was 34%. Of the fusion-positive cases, 71% showed deletion between the two genes, and 23% showed gain of the fusion. The fusion was associated with high Ki-67 staining (P=0.001), age at diagnosis (P=0.024), and tumor area (P=0.006), but not with Gleason score, T stage, M stage, prostate-specific antigen (PSA), or progression-free survival. Strong positive SPINK1 expression was found in 11% (21 of 186) of the biopsies. SPINK1-positive cases had significantly shorter progression-free survival compared with SPINK1-negative cases (P=0.001). The expression was not associated with any other clinicopathologic variables studied. In a multivariate analysis, SPINK1 expression showed independent prognostic value, with a relative risk of 2.3 (95% confidence interval, 1.1-4.6). SPINK1 expression and the fusion were not associated with each other. CONCLUSIONS: There was no association between TMPRSS2:ERG fusion and prognosis, suggesting that TMPRSS2:ERG rearrangement does not implicate hormone dependence of the cancer. SPINK1 expression, found in approximately 10% of prostate cancers, was associated with aggressive form of the disease and could serve as a biomarker in endocrine-treated prostate cancer.
