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Assessing the ERG rearrangement for clinincal use in patients with prostrate cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Sweden, close to 10 000 men are annually diagnosed with prostate cancer (PCa) and approximately 2400 men die of their disease each year. Today there is no reliable marker that can separate patients who will have an aggressive type of disease that requires treatment, from patients who will have a more indolent clinical course and can be left untreated. This further leads to the current problem of over treatment of men with PCa. Hence, there is an urgent need for reliable prognostic markers that can be used at time of diagnosis. With the discovery of recurrent gene rearrangements in PCa, most commonly ERG rearrangements, hope came that this aberration could play a role in diagnosis and/or prognosis of the disease.

The aim of this thesis was to investigate the clinical implication of ERG rearrangements in the management of PCa.

The work in this thesis supports the findings from previous studies, suggesting that the ERG rearrangement is a sign of a more aggressive type of cancer. The major findings are that in multifocal PCa, the ERG rearranged cancer foci are more prone to metastatic dissemination compared to foci without the ERG rearrangement and that patients harboring the ERG rearrangement have a faster disease progression leading up to earlier start of hormonal treatment. Furthermore, the results add an additional level of complexity in a subset of PCa tumors that harbor multiple gene rearrangements on the cellular level. The result also show that the newly available ERG antibody is highly predictive of ERG rearrangement and is appropriate to use when faced with limitations in tissue amounts.

The findings in this thesis indicate that the ERG rearrangement has a potential role in the clinical management of PCa but further studies arerequired.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2013. , p. 65
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 82
Keywords [en]
Prostate cancer, prognosis, biomarkers, ETS genes, ERG rearrangement, fluoroscence in situ hybridization
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-28471ISBN: 978-91-7668-918-9 (print)OAI: oai:DiVA.org:oru-28471DiVA, id: diva2:613024
Public defence
2013-04-26, Wilandersalen, Universitetssjukhuset, Grev Rosengatan 18, 703 62 Örebro, 09:31 (Swedish)
Opponent
Supervisors
Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2017-10-17Bibliographically approved
List of papers
1. Testing mutual exclusivity of ETS rearranged prostate cancer
Open this publication in new window or tab >>Testing mutual exclusivity of ETS rearranged prostate cancer
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2011 (English)In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 91, no 3, p. 404-412Article in journal (Refereed) Published
Abstract [en]

Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 50 fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements. Laboratory Investigation (2011) 91, 404-412; doi: 10.1038/labinvest.2010.179; published online 25 October 2010

Keywords
ETS (E26 transformation specific) rearrangements, TMPRSS2-ERG, heterogeneity, prostate cancer
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-28472 (URN)10.1038/labinvest.2010.179 (DOI)000287736500007 ()
Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2018-05-05Bibliographically approved
2. ERG Rearrangement Metastasis Patterns in Locally Advanced Prostate Cancer
Open this publication in new window or tab >>ERG Rearrangement Metastasis Patterns in Locally Advanced Prostate Cancer
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2010 (English)In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 75, no 4, p. 762-767Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES To interrogate multifocal prostate cancer (PCa) to determine its predilection for metastasis, using ERG rearrangement as marker of clonality. A hallmark of PCa is that distinct tumor foci may arise independently, which has important biological and clinical implications. Recent studies characterizing ERG-rearranged PCa possessing intrafocal homogeneity but interfocal heterogeneity support this hypothesis. METHODS We studied 26 patients who underwent prostatectomy and lymphadenectomy with at least 2 distinct PCa foci and 1 lymph node (LN) metastasis. Each focus was assessed for size, Gleason score, ERG rearrangement, and TMPRSS2-ERG transcript. RESULTS Fifteen of 26 cases exhibited interfocal homogeneity with regard to ERG rearrangement (ie, presence vs absence of ERG rearrangement). ERG rearrangement was present in all foci for 6 and absent in all foci for 9 cases. Two cases revealed interfocal heterogeneity with regard to rearrangement mechanism ( ie, rearrangement through insertion or deletion). Eight of 26 cases revealed interfocal heterogeneity with regard to rearrangement status. In all cases with at least 1 ERG rearranged focus, we found the corresponding LN metastasis harboring an ERG rearrangement. Interestingly, in a subset of cases the rearrangement status in the LN did not correspond to size or Gleason score. All but 2 ERG rearranged foci had detectable TMPRSS2-ERG transcript levels. CONCLUSIONS When multifocal PCa demonstrates both ERG-positive and ERG-negative foci, the positive foci have a greater predilection for metastasis. Larger studies are needed to confirm the potential additional risk an ERG rearranged focus confers on the likelihood of disease progression. UROLOGY 75: 762-767, 2010. (C) 2010 Elsevier Inc.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-28473 (URN)10.1016/j.urology.2009.10.010 (DOI)000276258300002 ()
Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2018-04-24Bibliographically approved
3. ERG rearrangement status and castration resistant prostate cancer: a prospective,population-based study
Open this publication in new window or tab >>ERG rearrangement status and castration resistant prostate cancer: a prospective,population-based study
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Overtreatment is a major concern in prostate cancer (PCa) management, as no adequate prognostic tool exists to separate indolent from aggressive disease at time of diagnosis. Androgen deprivation therapy (ADT) is the standard treatment of locally recurrent or metastatic PCa and although most men respond well to ADT initially, inevitably a resistance to the treatment develops. Men with tumor growth despite the androgen-depleted environment are considered to have castration resistant PCa (CRPC). After developing CRPC, the median survival time is typically less than two years. Since the initial discovery of ERG rearrangement in PCa, several studies have investigated the association between ERG rearrangement and clinical outcome of PCa with discrepant results. Few studies have examined the association between ERG rearrangement and CRPC, despite the fact that the most common fusion partners to ERG are androgen regulated. In this study we investigated the association between ERG status and time to CRPC.

We assessed the ERG status in a cohort of 220 men initially managed by watchful waiting and treated with ADT at disease progression. There was no statistically significant association between ERG status and time from start of ADT to CPRC, or start of ADT to PCa-specific death. However, men harboring the ERG rearrangement did have a significantly shorter time between time of diagnosis and start of hormonal treatment, compared to men without the rearrangement (HR: 1.81; 95% CI: 1.23- 2.65), suggesting that ERG rearrangement is indicative of a more aggressive subtype of PCa./p>

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-28474 (URN)
Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2017-10-17Bibliographically approved
4. A comparative study of ERG status assessment on DNA-, mRNA-, and proteinlevels using unique samples from a Swedish biopsy cohort
Open this publication in new window or tab >>A comparative study of ERG status assessment on DNA-, mRNA-, and proteinlevels using unique samples from a Swedish biopsy cohort
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The ERG rearrangement is identified in approximately 50% of prostate cancer (PCa) screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1- ERG fusions, all leading to an over expression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study we investigate ERG status on a series of diagnostic biopsies using DNA-, mRNA- and protein based assays. We formally compare three assay results (i.e. FISH, fusion mRNA and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG over expression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher’s exact test 9.50E-36) and 85.2% (138/162, Fisher’s exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in PCa.

Keywords
Prostate cancer, ERG rearrangement, Fluorescence in situ hybridization, Immunohistochemistry
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-28475 (URN)
Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2017-10-17Bibliographically approved

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