ERG expression in prostate cancer: The prognostic paradox

Taris, M.; Irani, Jacques; Blanchet, Pascal; Multigner, Luc; Cathelineau, Xavier; Fromont, Gaëlle

doi:10.1002/pros.22863

Cited by 33 publications

(26 citation statements)

References 33 publications

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“…Whether ETS fusion status in patients is associated with poor prognosis remains controversial and depends heavily on cohorts studied and definitions of disease aggressiveness [72, 60]. Results from the current study suggest that a stronger AR promotes ETV1-driven PCa progression, in accord with the androgen regulation of the transgene in mice and of relevance to fusion genes in patients.…”

Section: Discussionmentioning

confidence: 66%

Interaction of the Androgen Receptor, ETV1, and PTEN Pathways in Mouse Prostate Varies with Pathological Stage and Predicts Cancer Progression

et al. 2015

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To examine the impact of common somatic mutations in prostate cancer (PCa) on androgen receptor (AR) signaling, mouse models were designed to perturb sequentially the AR, ETV1 and PTEN pathways. Mice with "humanized" AR (hAR) alleles that modified AR transcriptional strength by varying polyglutamine tract (Q-tract) length were crossed with mice expressing a prostate-specific, AR-responsive ETV1 transgene (ETV1Tg). While hAR allele did not grossly affect ETV1-induced neoplasia, ETV1 strongly antagonized global AR regulation and repressed critical androgen-induced differentiation and tumor suppressor genes, such as Nkx3-1 and Hoxb13. When Pten was varied to determine its impact on disease progression, mice lacking one Pten allele (Pten+/−) developed more frequent prostatic intraepithelial neoplasia (PIN). Yet only those with the ETV1 transgene progressed to invasive adenocarcinoma. Furthermore, progression was more frequent with the short Q-tract (stronger) AR, suggesting that the AR, ETV1 and PTEN pathways cooperate in aggressive disease. On the Pten+/− background, ETV1 had markedly less effect on AR target genes. However, a strong inflammatory gene expression signature, notably upregulation of Cxcl16, was induced by ETV1. Comparison of mouse and human patient data stratified by presence of ETS fusion genes highlighted additional factors, some not previously associated with prostate cancer but for which targeted therapies are in development for other diseases. In sum, concerted use of these mouse models illuminates the complex interplay of AR, ETV1 and PTEN pathways in pre-cancerous neoplasia and early tumorigenesis, disease stages difficult to analyze in man.

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Section: Discussionmentioning

confidence: 66%

Interaction of the Androgen Receptor, ETV1, and PTEN Pathways in Mouse Prostate Varies with Pathological Stage and Predicts Cancer Progression

et al. 2015

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“…Studies analyzing the association between TMPRSS2-ERG states and clinicopathological parameters such as Gleason score and prognostic value have indicated conflicting results. Moreover, the clinical impact is still unclear, since while some authors have suggested a worse prognosis for fusion versus non-fusion cancers (13), other either found a favorable prognostic association (14, 15) or did not find any association with clinical outcome (16, 17). …”

Section: Discussionmentioning

confidence: 99%

“…In fact, ERG protein expression is the active form of the gene product and hence could be a better method in documenting any prognostic significance (13). Micheal Taris et al observed that ERG prevalence significantly increased from high grade PIN (17.5%) to PT2 tumors (27.5%) then to PT3 (43%) and metastases (53%) (13).…”

Section: Discussionmentioning

confidence: 99%

“…Micheal Taris et al observed that ERG prevalence significantly increased from high grade PIN (17.5%) to PT2 tumors (27.5%) then to PT3 (43%) and metastases (53%) (13). They showed that the association of ERG fusion with both advanced stage and better outcome in their study could be explained by the fact that fusion positive and fusion negative prostate cancer are likely to progress via different molecular pathways (13). …”

Section: Discussionmentioning

confidence: 99%

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Is There a Role for Genetic Information in Risk Assessment and Decision Making in Prostate Cancer?

et al. 2016

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ObjectivesProstate cancer is a neoplasm with a variable natural history and clinical behavior. There is much debate on the use of inherited genetic information in clinical application including risk assessment and treatment decisions. This study was performed to evaluate the relationship between clinical parameters of prostate cancer (PSA, Gleason score, and metastasis) and expression of NKX3.1, AMACR, TMPRSS2-ERG, ERG, and SPINK1 genes.MethodsNewly diagnosed cases of prostate cancer were selected for this study. Thirty four tissue samples were obtained via open radical prostatectomy and 9 samples were obtained via needle biopsy. Each tissue sample was sectioned into two parts, one used for detection of malignant changes and Gleason score determination, and the other immersed in RNA later solution (Qiagen). The expression of NKX3.1, AMACR, TMPRSS2-ERG, ERG, and SPINK1 genes were assessed by real-time PCR assay. Correlation between expression of each gene and PSA level, Gleason score, and presence of metastasis were examined.ResultsA total number of 43 specimens were studied, from which 9 were obtained from patients with metastatic prostate cancer. The expression of five examined genes had no correlation with PSA level and Gleason score. The expression of AMACR decreased in metastatic prostate cancer (P = 0.02). The expression of other genes showed no difference between metastatic and non-metastatic tumors (P > 0.1).ConclusionsGenetic information combined with clinical data can be useful in risk assessment and treatment planning. Based on the results of the current study, the decreased expression of AMACR was a sign of poor prognosis.

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“…This focus has to some extent overlooked the fact that the prevalence of these fusion products is lower for other ethnicities including AA, Japanese, and Chinese patients (109). The rate of TMPRSS2–ERG translocations in AA men appears to be significantly lower, in the range of 10–30% (110–113). AA patients, in addition to having lower incidence of TMPRSS2:ERG fusion, also have lower expression of ERG protein (109, 114, 115).…”

Section: Translocations Of the Tmprrs2 Gene Associate With Aggressmentioning

confidence: 92%

miRNAs as drivers of TMPRSS2-ERG negative prostate tumors in African American men

et al. 2017

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African Americans (AAs) who have PCa typically have more aggressive disease and make up a disproportionate number of the disease deaths, relative to European Americans (EAs). TMPRSS2 translocations, a common event in EA patients, are exploited in diagnostic and prognostic settings, whereas they are diminished in frequency in AA men. Thus, these patients with TMPRSS2 fusion-negative disease represent an under-investigated patient group. We propose that epigenetic events are a significant and alternative driver of aggressive disease in fusion-negative PCa. To reveal epigenetically governed microRNAs (miRNAs) that are enriched in fusion-negative disease and associated with aggressive in AA PCa, we leveraged both our experimental evidence and publically available data. These analyses identified 18 miRNAs that are differentially altered in fusion-negative disease, associated with DNA CpG methylation, and implicated in aggressive and AA PCas. Understanding the relationships between miRNA expression, upstream epigenetic regulation by DNA methylation, and downstream regulation of mRNA targets in fusion negative disease is imperative to understanding the biological basis of the racial health disparity in PCa.

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ERG expression in prostate cancer: The prognostic paradox

Cited by 33 publications

References 33 publications

Interaction of the Androgen Receptor, ETV1, and PTEN Pathways in Mouse Prostate Varies with Pathological Stage and Predicts Cancer Progression

Interaction of the Androgen Receptor, ETV1, and PTEN Pathways in Mouse Prostate Varies with Pathological Stage and Predicts Cancer Progression

Is There a Role for Genetic Information in Risk Assessment and Decision Making in Prostate Cancer?

miRNAs as drivers of TMPRSS2-ERG negative prostate tumors in African American men

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