| 1. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 2. |
- Fabris, Linda, et al.
(författare)
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The Potential of MicroRNAs as Prostate Cancer Biomarkers.
- 2016
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 70:2, s. 312-322
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Forskningsöversikt (refereegranskat)abstract
- Short noncoding RNAs known as microRNAs (miRNAs) control protein expression through the degradation of RNA or the inhibition of protein translation. The miRNAs influence a wide range of biologic processes and are often deregulated in cancer. This family of small RNAs constitutes potentially valuable markers for the diagnosis, prognosis, and therapeutic choices in prostate cancer (PCa) patients, as well as potential drugs (miRNA mimics) or drug targets (anti-miRNAs) in PCa management.
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| 3. |
- Hermans, Karin G, et al.
(författare)
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Overexpression of prostate-specific TMPRSS2(exon 0)-ERG fusion transcripts corresponds with favorable prognosis of prostate cancer.
- 2009
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 15:20, s. 6398-403
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight in the mechanism and clinical relevance of TMPRSS2-ERG expression in prostate cancer, we determined the specific characteristics of fusion transcripts starting at TMPRSS2 exon 1 and at a more upstream and less characterized exon 0.We used quantitative PCR analysis to investigate expression of wild-type TMPRSS2(exon 0) and TMPRSS2(exon 1) and of ERG fusion transcripts. Expression was tested in normal tissue samples, in prostate cancer cell lines and xenografts, and in fresh-frozen clinical prostate cancer samples (primary tumors and recurrences). Expression in clinical samples was correlated with disease progression.TMPRSS2(exon 0) and TMPRSS2(exon 1) transcripts were similarly androgen regulated in prostate cancer cell lines, but the expression levels of TMPRSS2(exon 1) were much higher. Comparison of expression in different tissues showed TMPRSS2(exon 0) expression to be much more prostate specific. In androgen receptor-positive prostate cancer xenografts, TMPRSS2(exon 1) transcripts were expressed at similar levels, but TMPRSS2(exon 0) transcripts were expressed at very variable levels. The same phenomenon was observed for TMPRSS2-ERG fusion transcripts. In clinical prostate cancers, the expression of TMPRSS2(exon 0)-ERG was even more variable. Expression of TMPRSS2(exon 0)-ERG transcripts was detected in 55% (24 of 44) of gene fusion-positive primary tumors but only in 15% (4 of 27) of gene fusion-positive recurrences and at much lower levels. Furthermore, in primary tumors, expression of TMPRSS2(exon 0)-ERG transcripts was an independent predictor of biochemical progression-free survival.The expression of TMPRSS2(exon 0)-ERG fusion transcripts in prostate cancer is associated with a less-aggressive biological behavior.
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| 4. |
- Iglesias-Gato, Diego, et al.
(författare)
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SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 35:1, s. 24-33
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Tidskriftsartikel (refereegranskat)abstract
- Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2) as mediator of the cross talk between androgens and GH signals in the prostate and its potential role as tumor suppressor in prostate cancer (PCa). We observed that SOCS2 protein levels assayed by immunohistochemistry are elevated in hormone therapy-naive localized prostatic adenocarcinoma in comparison with benign tissue. In contrast, however, castration-resistant bone metastases exhibit reduced levels of SOCS2 in comparison with localized or hormone naive, untreated metastatic tumors. In PCa cells, SOCS2 expression is induced by androgens through a mechanism that requires signal transducer and activator of transcription 5 protein (STAT5) and androgen receptor-dependent transcription. Consequentially, SOCS2 inhibits GH activation of Janus kinase 2, Src and STAT5 as well as both cell invasion and cell proliferation in vitro. In vivo, SOCS2 limits proliferation and production of IGF-1 in the prostate in response to GH. Our results suggest that the use of GH-signaling inhibitors could be of value as a complementary treatment for castration-resistant PCa. Summary: Androgen induced SOCS2 ubiquitin ligase expression and inhibited GH signaling as well as cell proliferation and invasion in PCa, whereas reduced SOCS2 was present in castration-resistant cases. GH-signaling inhibitors might be a complementary therapeutic option for advanced PCa.
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| 5. |
- Järemo, Helena, 1988-
(författare)
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MicroRNA expression profiles in prostate cancer bone metastases : functional effects of microRNA-23c, -375, and -4328
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non-coding microRNAs (miRNAs) function as post-transcriptional regulators of gene expression by interacting with messenger RNA. Dysregulation of miRNAs has many possible consequences, including tumor-suppressive or -promoting ones, and restoring or preventing the effects of miRNA alteration has therapeutic potential.Metastatic prostate cancer (PC) spreads to the bone and is treated with castration therapy. Eventually, metastases relapse into castration-resistant PC (CRPC) growth. Recently, our laboratory described metastatic PC subtypes, termed MetA-C, defined based on transcriptomic differences and linked to different morphology and prognosis. Patients with MetB metastases have particularly poor prognosis.The overall aim of the thesis was to identify novel biomarkers and therapeutic targets for metastatic PC, with a focus on miRNAs. The specific aims were to: (1) identify miRNAs associated with PC progression into bone metastasis, and their functional roles; (2) verify the MetA-C subtypes, their prognostic importance, and their relation to genetic profiles in independent validation cohorts; (3) explore miRNA expression profiles of PC bone metastases, specifically in relation to the MetA-C subtypes, and whether specific miRNAs show potential to inhibit the aggressive MetB subtype.Study 1: Differentially expressed miRNAs (n=79) were identified by microarray analysis by comparing miRNA levels in bone metastatic (n=14) or localized PC (n=7) samples to benign samples (n=7). Downregulation of miRNA-23c and -4328 was verified by qRT-PCR analysis, including a larger cohort of bone metastases (n=67). Overexpression of miRNA-23c or -4328 in PC cells resulted in attenuated cell growth in vitro. High levels of miRNA-23c were detected in extracellular vesicles shed from overexpressing cells. Overexpression of miRNA-23c did not obviously affect tumor growth or angiogenesis in vivo. Study 2: The existence and prognostic value of the MetA-C subtypes was verified by transcriptomic analysis of bone metastasis samples (n=103), and by subtyping publicly available data from metastatic samples (n=573) from external patient cohorts. The MetB subtype was associated with high tumor-cell proliferation, low androgen receptor activity, and poor prognosis in all cohorts, and provided independent prognostic information in addition to genetic aberrations.Study 3: The miRNA profiles of 96 bone metastasis samples from Study 2 were examined using microarray analysis. Four sample clusters not obviously related to the MetA-C subtypes were observed. Expression levels of miRNA-375, however, were inversely related to MetB. MiRNA-375 overexpression in C4-2B resulted in a cellular switch of subtype, from being dominant MetB to dominant MetA. In parallel, reduced cell growth and signs of increased cell adhesion were observed.In conclusion, altered miRNA profiles may contribute to progression of PC into bone metastasis, and to the development of different metastasis subtypes. The MetB subtype is associated with poor prognosis and low expression of miRNA-375. Therapy stratification based on the MetA-C subtypes should be considered in the future. Restoration of miRNA-375 in MetB tumors may offer a novel treatment option.
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| 6. |
- Kalra, Hina, et al.
(författare)
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Vesiclepedia : a compendium for extracellular vesicles with continuous community annotation
- 2012
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Ingår i: PLoS biology. - : Public library of science. - 1544-9173 .- 1545-7885. ; 10:12, s. e1001450-
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
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| 7. |
- Larne, Olivia, et al.
(författare)
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miQ - a novel microRNA based diagnostic and prognostic tool for prostate cancer.
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 132:12, s. 2867-2875
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Tidskriftsartikel (refereegranskat)abstract
- Today, the majority of prostate tumours are detected at early stages with uncertain prognosis. Therefore, we set out to identify early predictive markers of prostate cancer with aggressive progression characteristics. We measured the expression of microRNAs (miRNA) using qRT-PCR in FFPE prostatic tissue samples from a Swedish cohort of 49 patients with prostate cancer and 25 without cancer and found eight of 14 preselected miRNAs to discriminate between the two groups. Subsequently four discriminatory miRNAs were combined to a quota, denoted the miRNA index quote (miQ); ((miR-96-5p x miR-183-5p)/(miR-145-5p x miR221-5p)). The advantage using a quote is increased discrimination, no need for house-keepings, and most important it may be an advantage considering the heterogeneity of the disease. miQ was found to successfully predict diagnosis (p<0.0001) with high accuracy (AUC=0.931) that was verified in an independent Dutch cohort and three external cohorts, and significantly outperforming PSA. Importantly, miQ also has prognostic power to predict aggressiveness of tumours (AUC=0.895), metastatic statues (AUC=0.827), and overall survival (p=0.0013, Wilcoxon test HR=6.5, median survival 2 versus 5 years), verified in the Dutch cohort. In this preliminary study we propose that miQ has potential to be used as a clinical tool for prostate cancer diagnosis and as a prognostic marker of disease progression. © 2012 Wiley Periodicals, Inc.
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| 8. |
- Tomlins, Scott A., et al.
(författare)
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ETS Gene Fusions in Prostate Cancer: From Discovery to Daily Clinical Practice
- 2009
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 56:2, s. 275-286
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Forskningsöversikt (refereegranskat)abstract
- Context. In 2005, fusions between the androgen-regulated transmembrane protease serine 2 gene, TMPRSS2, and E twenty-six (ETS) transcription factors were discovered in prostate cancer. Objective: To review advances in our understanding of ETS gene fusions, focusing on challenges affecting translation to clinical application. Evidence acquisition: The PubMed database was searched for reports on ETS fusions in prostate cancer. Evidence synthesis: Since the discovery of ETS fusions, novel 5' and 3' fusion partners and multiple splice isoforms have been reported. The most common fusion, TMPRSS2:ERG, is present in approximately 50% of prostate-specific antigen (PSA)-screened localized prostate cancers and in 15-35% of population-based cohorts. ETS fusions can be detected noninvasively in the urine of men with prostate cancer, with a specificity rate in PSA-screened cohorts of >90%. Reports from untreated population-based cohorts suggest an association between ETS fusions and cancer-specific death and metastatic spread. In retrospective prostatectomy cohorts, conflicting results have been published regarding associations between ETS fusions and cancer aggressiveness. In addition to serving as a potential biomarker, tissue and functional studies suggest a specific role for ETS fusions in the transition to carcinoma. Finally, recent results suggest that the 5' and 3' ends of ETS fusions as well as downstream targets may be targeted therapeutically. Conclusions: Recent studies suggest that the first clinical applications of ETS fusions are likely to be in noninvasive detection of prostate cancer and in aiding with difficult diagnostic cases. Additional studies are needed to clarify the association between gene fusions and cancer aggressiveness, particularly those studies that take into account the multifocal and heterogeneous nature of localized prostate cancer. Multiple promising strategies have been identified to potentially target ETS fusions. Together, these results suggest that ETS fusions will affect multiple aspects of prostate cancer diagnosis and management. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 9. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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