Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor ERG is highly upregulated in the majority of prostate cancers due to chromosomal fusion of the androgen responsive promoter of TMPRSS2 to the ERG reading frame. Our aim was to identify this gene fusion in urine samples from prostate cancer patients prior to radical treatment and to compare fusion status with clinicopathological variables. Urine fractions from 55 patients (with and without prior prostatic massage) were analyzed for the presence of TMPRSS2:ERG isoforms using real-time qPCR. Sixty-nine percent of urine samples following prostatic massage were positive for TMPRSS2:ERG isoforms a or b, five out of which were positive for both, vs 24% of samples obtained without prior massage. Isoform a seems to be most prevalent and some patients may be positive for more than one fusion variant, reflecting the multifocality of prostate cancer. Prostatic massage prior to sampling, analysis of pelleted urine material and detection of cDNA provided the highest sensitivity. Positive statistical correlations were identified between TMPRSS2:ERG fusion and high s-PSA, pathological stage and Gleason score. Our findings contribute to the increasing elucidation of the role of TMPRSS2:ERG in the development of prostate cancer.
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PMID:TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis. 1966 28

Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer.
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PMID:Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer. 1977 49

The somatic fusion of TMPRSS2 to ETS oncogenes is a common event in prostate cancer (PCa). We hypothesized that defects in DNA repair may lead to an increase of chromosomal rearrangements and thus to the occurrence of ETS oncogene fusion. We have previously conducted a genome-wide linkage analysis in TMPRSS2-ERG fusion-positive PCa families, revealing potential susceptibility loci on chromosomes 5q14, 9q21, 10q26, 11q24, 12q15, 13q12, 18q, and Xq27. In the present study, nine candidate genes from these regions were selected from the context of DNA repair and screened for mutations in TMPRSS2-ERG fusion-positive families. Thirteen nonsynonymous variants, 5 of which had a minor allele frequency of <0.05, were genotyped in 210 familial cases, 47 of which with a known TMPRSS2-ERG status, 329 sporadic cases, and 512 controls. Significant association of TMPRSS2-ERG fusion-positive PCa was found with rare variants in the genes for POLI [variant F532S: P = 0.0011; odds ratios (OR), 4.62; 95% confidence interval (95% CI), 1.84-11.56] and ESCO1 (variant N191S: P = 0.0034; OR, 4.27; 95% CI, 1.62-11.28). Additional findings, regardless of TMPRSS2-ERG status, were the overrepresentation of a rare BRCA2 variant (V2728I: P = 0.03; OR, 6.16; 95% CI, 1.19-32.00) in familial PCa and of a common allele of RMI1 (variant N455S: P = 0.02; OR, 1.33; 95% CI, 1.04-1.70) in unselected PCa cases. The DNA repair genes POLI and ESCO1 are proposed as susceptibility genes for TMPRSS2-ERG fusion-positive PCa that warrant further investigation.
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PMID:Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes. 1986 17

Gene fusions play a critical role in cancer progression. The mechanisms underlying their genesis and cell type specificity are not well understood. About 50% of human prostate cancers display a gene fusion involving the 5' untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an erythroblast transformation-specific (ETS) transcription factor. By studying human prostate cancer cells with fluorescence in situ hybridization, we show that androgen signaling induces proximity of the TMPRSS2 and ERG genomic loci, both located on chromosome 21q22.2. Subsequent exposure of the cells to gamma irradiation, which causes DNA double-strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling.
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PMID:Induced chromosomal proximity and gene fusions in prostate cancer. 1993 9

The identification of fusion genes provides new insights into the initial mechanisms of molecular events implicated in the prostate cancer tumorigenesis. The presence of TEMPRSS2-ETS fusion in up to half of all human prostate cancer makes it perhaps the most common genetic rearrangement in human epithelial tumors. Some data suggest that TMPRSS2-ERG fusion prostate cancers have a more aggressive phenotype, which may affect cancer progression and outcome in localized tumors treated with prostatectomy. This discovery should pave the way towards future targeted therapies.
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PMID:[Fusion genes and prostate cancer. From discovery to prognosis and therapeutic perspectives]. 1994 66

Emerging biological observations in prostate cancer provide the opportunity for the development of novel approaches to prevention, detection and treatment. Two observations selected for discussion in this review revolve around the mechanisms of action of signaling through the androgen receptor (AR) and the TMPRSS2:ERG chromosomal rearrangement, a fusion protein seen in nearly 50% of prostate cancers. Despite being called androgen-independent, these prostate cancers continue to depend on AR signaling despite low serum androgen levels. AR reactivation in recurrent tumors is hypothesized to occur through multiple mechanisms: AR amplification, AR mutation, active AR signaling (despite low levels of androgen), AR coactivators, ligand-independent AR activation, enhanced local production of androgens, alternative sources of androgen and upregulation in antiapoptotic genes in prostate cancer cells. A major breakthrough in prostate cancer was the identification of recurrent fusions between the androgen-regulated gene, TMPRSS2 and the v-ets erythroblastosis virus E26 oncogene homolog, ERG. This fusion has been identified as a common molecular event in prostate cancer, seen in approximately 50% of primary prostate cancer. It seems clear that this fusion gene plays an early role in prostate cancer development and/or progression, and ongoing work is being performed to elucidate the association between this fusion transcript and cancer aggressiveness.
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PMID:Emerging biological observations in prostate cancer. 2001 89

Prostate cancer is the most commonly diagnosed malignancy in males in the Western world. This review focuses on advances in biomarker discovery for prostate cancer by microarray profiling of mRNA and microRNA expression. Novel biomarkers are strongly needed to enable more accurate detection of prostate cancer, improve prediction of tumor aggressiveness and facilitate discovery of new therapeutic targets for tailored medicine. Promising molecular markers identified from gene expression profiling studies include AMACR, EZH2, TMPRSS2-ERG, miR-221 and miR-141, which are described in more detail. In addition, a compilation of prognostic gene expression signatures for prediction of prostate cancer patient outcome is provided, and their possible clinical utility is discussed. Furthermore, limitations in the application of microarray-based expression profiling for identification of prostate cancer biomarkers are addressed.
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PMID:Discovery of prostate cancer biomarkers by microarray gene expression profiling. 2001 22

The majority of prostate cancers harbor recurrent gene fusions between the hormone-regulated TMPRSS2 and members of the ETS family of transcription factors, most commonly ERG. Prostate cancer with ERG rearrangements represent a distinct sub-class of tumor based on studies reporting associations with histomorphologic features, characteristic somatic copy number alterations, and gene expression signatures. This study describes the frequency of ERG rearrangement prostate cancer and three 5 prime (5') gene fusion partners (ie, TMPRSS2, SLC45A3, and NDRG1) in a large prostatectomy cohort. ERG gene rearrangements and mechanism of rearrangement, as well as rearrangements of TMPRSS2, SLC45A3, and NDRG1, were assessed using fluorescence in situ hybridization (FISH) on prostate cancer samples from 614 patients treated using radical prostatectomy. ERG rearrangement occurred in 53% of the 540 assessable cases. TMPRSS2 and SLC45A3 were the only 5' partner in 78% and 6% of these ERG rearranged cases, respectively. Interestingly, 11% of the ERG rearranged cases showed concurrent TMPRSS2 and SLC45A3 rearrangements. TMPRSS2 or SLC45A3 rearrangements could not be identified for 5% of the ERG rearranged cases. From these remaining cases we identified one case with NDRG1 rearrangement. We did not observe any associations with pathologic parameters or clinical outcome. This is the first study to describe the frequency of SLC45A3-ERG fusions in a large clinical cohort. Most studies have assumed that all ERG rearranged prostate cancers harbor TMPRSS2-ERG fusions. This is also the first study to report concurrent TMPRSS2 and SLC45A3 rearrangements in the same tumor focus, suggesting additional complexity that had not been previously appreciated. This study has important clinical implications for the development of diagnostic assays to detect ETS rearranged prostate cancer. Incorporation of these less common ERG rearranged prostate cancer fusion assays could further increase the sensitivity of the current PCR-based approaches.
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PMID:Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort. 2011 10

Inhibitors of 5alpha-reductase (SRD5A) that lower intraprostatic levels of dihydrotestosterone (DHT) reduce the overall incidence of prostate cancer (PCa), but there is significant variation in chemopreventive activity between individual men. In seeking molecular alterations that might underlie this variation, we compared gene expression patterns in patients with localized PCa who were randomized to prostatectomy alone versus treatment with two different doses of the SRD5A inhibitor dutasteride. Prostatic levels of DHT were decreased by >90% in both dutasteride-treated patient groups versus the untreated patient group. Despite significant and uniform suppression of tissue DHT, unsupervised clustering based on prostatic gene expression did not discriminate these groups. However, subjects could be resolved into distinct cohorts characterized by high or low expression of genes regulated by the androgen receptor (AR), based solely on AR transcript expression. The higher-dose dutasteride treatment group was found to include significantly fewer cancers with TMPRSS2-ERG genetic fusions. Dutasteride treatment was associated with highly variable alterations in benign epithelial gene expression. Segregating subjects based on expression of AR and androgen-regulated genes revealed that patients are differentially sensitive to SRD5A inhibition. Our findings suggest that AR levels may predict the chemopreventive efficacy of SRD5A inhibitors.
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PMID:Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention. 2012 90

Our previous work identified a chromosomal translocation t(4;6) in prostate cancer cell lines and primary tumors. Using probes located on 4q22 and 6q15, the breakpoints identified in LNCaP cells, we performed fluorescence in situ hybridization analysis to detect this translocation in a large series of clinical localized prostate cancer samples treated conservatively. We found that t(4;6)(q22;q15) occurred in 78 of 667 cases (11.7%). The t(4;6)(q22;q15) was not independently associated with patient outcome. However, it occurs more frequently in high clinical T stage, high tumor volume specimens and in those with high baseline PSA (P=0.001, 0.001 and 0.01, respectively). The t(4;6)(q22;q15) occurred more frequently in samples with two or more TMPRSS2:ERG fusion genes caused by internal deletion than in samples without these genomic alterations, but this correlation is not statistically significant (P=0.0628). The potential role of this translocation in the development of human prostate cancer is discussed.
Prostate Cancer Prostatic Dis 2010 Jun
PMID:The identification of chromosomal translocation, t(4;6)(q22;q15), in prostate cancer. 2017 23


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