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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG and ETV1, were identified as outliers in prostate cancer. We identified recurrent gene fusions of the 5' untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlier expression. By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1. Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. These results have implications in the development of carcinomas and the molecular diagnosis and treatment of prostate cancer.
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PMID:Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. 1749 20

Genes playing a role in carcinogenesis have often been identified through analysis of recurrent chromosomal rearrangements. Although such rearrangements are well known in leukemias, lymphomas, and sarcomas, they have not been well characterized in carcinomas. In the October 28, 2005 issue of Science, a study by Tomlins et al. uses bioinformatics techniques to identify candidate oncogenic chromosomal changes based on analysis of outlier gene expression. The authors determined that two ETS transcription factors, ERG and ETV1 were outliers in prostate cancer. The group reports recurrent fusions of the 5' untranslated region of the TMPRSS2 gene to ERG and ETV1 in the majority of prostate cancer samples containing the outlier expression. In cell lines containing the fusion gene, androgen appears to play a role in mediating ETS overexpression. This fusion gene product may play an important role in the development, diagnosis, and treatment of prostate cancer.
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PMID:ETS-TMPRSS2 fusion gene products in prostate cancer. 1657

Although common in hematologic and mesenchymal malignancies, recurrent gene fusions have not been well characterized in epithelial carcinomas. Recently, using a novel bioinformatic approach, we identified recurrent gene fusions between TMPRSS2 and the ETS family members ERG or ETV1 in the majority of prostate cancers. Here, we interrogated the expression of all ETS family members in prostate cancer profiling studies and identified marked overexpression of ETV4 in 2 of 98 cases. In one such case, we confirmed the overexpression of ETV4 using quantitative PCR, and by rapid amplification of cDNA ends, quantitative PCR, and fluorescence in situ hybridization, we show that the TMPRSS2 (21q22) and ETV4 (17q21) loci are fused in this case. This result defines a third molecular subtype of prostate cancer and supports the hypothesis that dysregulation of ETS family members through fusions with TMRPSS2 may be an initiating event in prostate cancer development.
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PMID:TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. 1658 60

The recent description of novel recurrent gene fusions in approximately 80% of prostate cancer (PCa) cases has generated increased interest in the search for new translocations in other epithelial cancers and emphasizes the importance of understanding the origins and biologic implications of these genomic rearrangements. Analysis of 15 PCa cases by reverse transcription-polymerase chain reaction was used to detect six ERG-related gene fusion transcripts with TMPRSS2. No TMPRSS2/ETV1 chimeric fusion was detected in this series. Three-color fluorescence in situ hybridization confirms that TMPRSS2/ERG fusion may be accompanied by a small hemizygous sequence deletion on chromosome 21 between ERG and TMPRSS2 genes. Analysis of genomic architecture in the region of genomic rearrangement suggests that tracts of microhomology could facilitate TMPRSS2/ERG fusion events.
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PMID:Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement. 1682 92

Although multiple recurrent chromosomal alterations have been identified in prostate cancer cells, the specific genes driving the apparent selection of these changes remain largely unknown. In part, this uncertainty is due to the limited resolution of the techniques used to detect these alterations. In this study, we applied a high-resolution genome-wide method, Affymetrix 100K SNP mapping array, to screen for somatic DNA copy number (CN) alterations among 22 pairs of samples from primary prostate cancers and matched nonmalignant tissues. We detected 355 recurrent deletions and 223 recurrent gains, many of which were novel. As expected, the sizes of novel alterations tend to be smaller. Importantly, among tumors with increasing grade, Gleason sum 6, 7, and 8, we found a significant trend of larger number of alterations in the tumors with higher grade. Overall, gains are significantly more likely to occur within genes (74%) than are deletions (49%). However, when we looked at the most frequent CN alterations, defined as those in > or =4 subjects, we observed that both gains (85%) and deletions (57%) occur preferentially within genes. An example of a novel, recurrent alteration observed in this study was a deletion between the ERG and TMPRSS2 genes on chromosome 21, presumably related to the recently identified fusion transcripts from these two genes. Results from this study provide a basis for a systematic and comprehensive cataloging of CN alterations associated with grades of prostate cancer, and the subsequent identification of specific genes that associated with initiation and progression of the disease. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat
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PMID:Comprehensive assessment of DNA copy number alterations in human prostate cancers using Affymetrix 100K SNP mapping array. 1689 47

Prostate cancer is a common and clinically heterogeneous disease with marked variability in progression. The recent identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), suggests a mechanism for overexpression of the ETS genes in the majority of prostate cancers. In the current study using fluorescence in situ hybridization (FISH), we identified the TMPRSS2:ERG rearrangements in 49.2% of 118 primary prostate cancers and 41.2% of 18 hormone-naive lymph node metastases. The FISH assay detected intronic deletions between ERG and TMPRSS2 resulting in TMPRSS2:ERG fusion in 60.3% (35 of 58) of the primary TMPRSS2:ERG prostate cancers and 42.9% (3 of 7) of the TMPRSS2:ERG hormone-naive lymph node metastases. A significant association was observed between TMPRSS2:ERG rearranged tumors through deletions and higher tumor stage and the presence of metastatic disease involving pelvic lymph nodes. Using 100K oligonucleotide single nucleotide polymorphism arrays, a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2-3 was identified with two distinct subclasses distinguished by the start point of the deletion at either 38.765 or 38.911 Mb. This study confirms that TMPRSS2:ERG is fused in approximately half of the prostate cancers through deletion of genomic DNA between ERG and TMPRSS2. The deletion as cause of TMPRSS2:ERG fusion is associated with clinical features for prostate cancer progression compared with tumors that lack the TMPRSS2:ERG rearrangement.
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PMID:TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. 1695 Nov 39

Recent studies have reported that the majority of prostate cancers express fusion genes in which the 5' region of the androgen-regulated TMPRSS2 gene is fused to an ETS family transcription factor, most commonly the ERG gene. We have characterized in detail the expression of TMPRSS2/ERG fusion mRNAs and correlated the isoforms expressed and expression levels with clinical outcome in cancers from men undergoing radical prostatectomy. Overall, 59% of clinically localized prostate cancers express the TMPRSS2/ERG fusion gene, confirming the initial observations of high frequency expression of this fusion mRNA in prostate cancer. There was significant variation in the alternatively spliced isoforms expressed in different cancers. Expression of an isoform, in which the native ATG in exon 2 of the TMPRSS2 gene is in frame with exon 4 of the ERG gene, was associated with clinical and pathologic variables of aggressive disease. Expression of other isoforms, in which the native ERG ATG in exon 3 was the first in-frame ATG, was associated with seminal vesicle invasion, which is correlated with poor outcome following radical prostatectomy. Cancers not expressing these isoforms tended to express higher levels of fusion mRNAs, and in this group, higher expression levels of fusion mRNA were present in cancers with early prostate-specific antigen recurrence. Thus, both the isoforms of TMPRSS2/ERG fusions expressed and expression level may affect prostate cancer progression.
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PMID:Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. 1695 Nov 41

Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We describe the use of a novel bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression called COPA (cancer outlier profile analysis). We demonstrate how this approach led to the identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3), an androgen regulated gene, with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4(17q21). These novel gene fusions suggest a mechanism for overexpression of the ETS genes in the majority of prostate cancers identified through PSA screening. Considering the high incidence of prostate cancer and the high frequency of this gene fusion, the TMPRSS2-ETS gene fusions are the most common genetic aberration so far described in human malignancies. The clinical implications of this discovery are significant for diagnosis and potentially for the development of targeted therapy.
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PMID:Bioinformatics approach leads to the discovery of the TMPRSS2:ETS gene fusion in prostate cancer. 1698 28

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease.
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PMID:Improving the outcome of patients with castration-resistant prostate cancer through rational drug development. 1698 3

TMPRSS2-ETS gene fusions have been found recurrently in prostate carcinomas, but not in the presumed precursor lesion, high-grade prostatic intraepithelial neoplasia (HGPIN). However, HGPIN lesions may share chromosomal changes with prostate cancer. To determine the relative order of genetic events in prostate carcinogenesis, we have analyzed 34 prostate carcinomas, 19 paired HGPIN lesions, 14 benign prostate hyperplasias, and 11 morphologically normal prostatic tissues for TMPRSS2-ERG and TMPRSS2-ETV1 rearrangements and genomic imbalances. TMPRSS2 exon 1 was fused in-frame with ERG exon 4 in 17 of 34 (50%) prostate carcinomas and in 4 of 19 (21%) HGPIN lesions, but in none of controls. The findings were further validated by sequencing analysis and by the real-time polymerase chain reaction quantification of TMPRSS2-ERG fusion transcript and the ERG exons 5/6:exons 1/2 expression ratio. Chromosome copy number changes were detected by comparative genomic hybridization in 42% of clinically confined carcinomas and in none of the 16 HGPIN lesions analyzed. We demonstrate for the first time that the TMPRSS2-ERG fusion gene can be detected in a proportion of HGPIN lesions and that this molecular rearrangement is an early event that may precede chromosome-level alterations in prostate carcinogenesis.
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PMID:TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. 1703 99


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