| 1. |
- Braegelmann, Johannes, et al.
(författare)
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Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
- 2017
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research Inc.. - 1078-0432 .- 1557-3265. ; 23:7, s. 1829-1840
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches.Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq.Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancerwasmarked by high expression of CDK19. In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8were present inmetastases. In vitro, inhibition ofCDK19 and CDK8 by knockdown or treatment with a selective CDK8/ CDK19 inhibitor significantly decreased migration and invasion.Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer.
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| 2. |
- George, Julie, et al.
(författare)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Tidskriftsartikel (refereegranskat)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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| 3. |
- Merz, Constanze, et al.
(författare)
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IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2
- 2016
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Ingår i: American Journal of Pathology. - New York, USA : Elsevier. - 0002-9440 .- 1525-2191. ; 186:4, s. 974-984
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the clinicopathologic data of ERG and IL-6 using immunohistochemical double staining and correlated the read-out with clinicopathologic data. Expression of ERG and IL-6 correlated strongly in prostate tissue samples. Forced expression of ERG in prostate tumor cell lines resulted in significantly increased secretion of IL-6, whereas the down-regulation of ERG decreased IL-6 secretion. By dissecting the underlying mechanism in prostate tumor cell lines we show the ERG-mediated up-regulation of the prostanoid receptors EP2 and EP3. The prostanoid receptor EP2 was overexpressed in human prostate cancer tissue. Furthermore, the proliferation rate and IL-6 secretion in DU145 cells was reduced after treatment with EP2-receptor antagonist. Collectively, our study shows that the expression of ERG in prostate cancer is linked to the expression of IL-6 mediated by the prostanoid receptor EP2.
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| 4. |
- Offermann, Anne, et al.
(författare)
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TRIM24 as an independent prognostic biomarker for prostate cancer
- 2019
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Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 37:9
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Simply applicable biomarkers for prostate cancer patients predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen receptor signaling and to correlate with an aggressive prostate cancer phenotype. Based on these data, we proofed TRIM24 as a prognostic biomarker for risk stratification.Materials and Methods: We performed TRIM24 immunohistochemistry on 2 independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases, and 129 benign prostatic samples from 497 patients as well as on 246 prostate needle biopsies. Expression data were correlated with clinic-pathological data including biochemical recurrence-free survival (bRFS) as endpoint.Results: Benign samples show no or low TRIM24 expression in 94%, while tumor tissues demonstrate significant higher levels. Strongest expression is observed in advanced and metastatic tumors. In multivariate analyses, TRIM24 up-regulation on radical prostatectomy specimens correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher grade group, positive nodal status and extraprostatic tumor growth. TRIM24 assessment on prostate needle biopsies taken prior to treatment decision at time of initial diagnosis significantly correlates with recurrence after surgery.Conclusion: Using 2 large independent radical prostatectomy specimen cohorts, we found that TRIM24 expression predicts patients' risk to develop disease recurrence with high accuracy and independent from other established biomarkers. Further, this is the first study exploring TRIM24 expression on prostate needle biopsies which represents the clinically relevant tissue type on which biomarkers guide treatment decisions. Thus, we strongly suggest introducing TRIM24 evaluation in prostate needle biopsies in clinical routine as an inexpensive and simple immunohistochemical test.
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| 5. |
- Offermann, Anne, et al.
(författare)
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TRIM24 as Independent Prognostic Marker in Prostate Cancer
- 2018
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Ingår i: Modern Pathology. - : Nature Publishing Group. - 0893-3952 .- 1530-0285. ; 31:Suppl. 2, s. 372-373
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Simply applicable biomarkers for prostate cancer (PCa) predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen-receptor signaling and to correlate with poor outcome. Based on these data, we validated TRIM24 as a prognostic biomarker for PCa.Design: We performed TRIM24 immunohistochemistry on two independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases and 129 benign prostatic samples from 497 patients. Expression data were correlated with clinic-pathological data including biochemical recurrence free survival (bRFS) as endpoint.Results: Benign samples show no/low TRIM24 expression in 94%, while tumors demonstrate significantly higher levels. Strongest expression is observed in metastatic tumors. In multivariate analyses, TRIM24 up-regulation correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher Grade Group, positive nodal status and extraprostatic tumor growth.Conclusions: Using two large independent cohorts, we found that TRIM24 expression predicts patients’ risk to develop disease recurrence with high accuracy and independently from other established prognostic markers. To our knowledge, TRIM24 is the first prognostic biomarker to be independent, accurate and reproducible on three different primary PCa cohorts. Thus, we strongly suggest introducing TRIM24 in clinical routine as a simple immunohistochemical test.
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