Der Einsatz des präoperativen Mamma-MRTs bei Patientinnen mit primärem Mammakarzinom wird weiterhin kritisch diskutiert. Dies beruht insbesondere auf Bedenken hinsichtlich einer möglichen Überdiagnostik sowie Übertherapie bei falsch-positiven Ergebnissen.

BACKGROUND: Approximately half of the prostate carcinomas are characterized by a chromosomal rearrangement fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the role and impact of the ERG rearrangement and protein expression on the progression to castration-resistant (CR) disease.METHODS: We used a tissue microarray (TMA) constructed from 114 hormone naive (HN) and 117 CR PCs. We analyzed the ERG rearrangement status by fluorescence in situ hybridization and the expression profiles of ERG, androgen receptor (AR) and the proliferation marker Ki67 by immunohistochemistry.RESULTS: Nearly half of the PC tissue specimens (HN: 38%, CR: 46%) harbored a TMPRSS2-ERG gene fusion. HN PCs with positive translocation status showed increased tumor cell proliferation (P<0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in HN and CR PCs (both P<0.0001). Remarkably, the study revealed a subgroup (26%) of CR PCs with ERG rearrangement but without any detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and androgen-regulated serum PSA (both P<0.05).CONCLUSIONS: In this study, we identified a subgroup of ERG-rearranged CR PCs without detectable ERG protein expression. Our results suggest that this subgroup could represent CR PCs with a dispensed AR pathway. These tumors might represent a thus far unrecognized subset of patients with AR-independent CR PC who may not benefit from conventional therapy directed against the AR pathway.

The mediator complex is an evolutionary conserved key regulator of transcription of protein‐coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration‐resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF‐β3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPCMET) and 70% of local‐recurrent CRPC (CRPCLOC), in contrast to low frequencies in androgen‐sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF‐β signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p‐SMAD3 to the nucleus as well as TGF‐β‐enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen‐dependent and ‐independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic‐resistant diseases, and not restricted to our disease model.

Der Nutzen der präoperativen MRT-Diagnostik bei gesichertem Mammakarzinom wird aktuell kontrovers bewertet. Hierbei ist insbesondere die erhöhte Mastektomierate nach präoperativen Mamma-MRTs ein zentraler Kritikpunkt. Ein möglicher Nutzen der MRT-Diagnostik in Subgruppen, die prognostische Relevanz und die Vorteile einer Evaluation der kontralateralen Brust sind hierbei noch nicht abschließend geklärt.

The recently detected TMPRSS2-ERG fusion gene was revealed as a recurrent and prevalent prostate cancer (PCa)-specific event, potentially qualifying it for clinical use. To detect this alteration, fluorescence in situ hybridization (FISH) is the method of choice. However, FISH has some disadvantages for widespread adoption in clinical practice. Subsequently, chromogenic in situ hybridization, which uses organic chromogens, and enzymatic metallography silver in situ hybridization have emerged as promising bright-field alternatives. Compared with chromogenic in situ hybridization, silver in situ hybridization signals are very distinct and superior with regard to signal clarity and resolution, but the method excludes multicolor protocols. Based on the ERG break-apart FISH assay, we established a dual-color ERG break-apart assay using combined chromogenic in situ hybridization and silver in situ hybridization (CS-ISH) and compared these results with those obtained by FISH. We assessed 178 PCa and 10 benign specimens for their ERG rearrangement status by applying dual-color FISH and CS-ISH ERG break-apart assays to consecutive sections. We observed a highly significant concordance (97.7%) between FISH- and CS-ISH-based results (Pearson's correlation coefficient = 0.955, P < 0.001). Our findings demonstrate that the ERG rearrangement status can reliably be assessed by CS-ISH. Further, the CS-ISH technique combines the accuracy and precision of FISH with the ease of bright-field microscopy. This tool allows a much broader spectrum of applications in which to study the biological role and clinical use of ERG rearrangements in PCa.

Review on ERG (v-ets erythroblastosis virus E26 oncogene like (avian)), with data on DNA, on the protein encoded, and where the gene is implicated.

Abstract Introduction: Approximately half of the diagnosed prostate carcinomas (PC) are characterized by a chromosomal rearrangement fusing the androgen regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the impact of this translocation on the expression of the ERG gene in hormone-naïve (untreated) and castration-resistant prostate cancers and to define the influence of AR protein expression and genomic amplification in this context. Methods: We constructed a tissue microarray (TMA) containing 915 tissue cores from 107 hormone-naïve PC and from 101 castration-resistant (CR) PC. In addition, we included 56 specimens from distant metastases. We analyzed the TMPRSS2-ERG translocation status by fluorescence in-situ hybridization and the expression profiles of ERG, AR and the proliferation marker Ki67 by immunohistochemistry. Results: Nearly half of the analyzed PC tissue specimens (untreated: 38%, castration-resistant: 46%) harbored a TMPRSS2-ERG gene fusion. Untreated PC with positive translocation status showed increased tumor cell proliferation (p < 0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in untreated, as well as in castration-resistant PC (both p < 0.0001). However, we detected a subgroup (26%) of CR PCs with the gene fusion, but without detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and of the androgen regulated serum PSA (both p>0.05). Conclusions: This comprehensive study comparing the TMPRSS2-ERG gene and ERG protein expression status in a large cohort of hormone-naïve and CR PC, identifies a subgroup of translocated CR PCs without ERG protein expression. Our results suggest that this subgroup may represent CR PCs with a dispensed AR pathway. Further analyses may help to explain if these tumors represent a distinct subgroup of AR independent CR PCs. Citation Format: Shyh-Han Tan, I. Sesterhenn, S. Srivastava, L. Bubendorf, C. Ruiz, M. Braun, V.J. Scheble, T. Zellweger, C.A. Rentsch, A. Bachmann, Albert Dobi, S. Perner. Comprehensive analysis of the TMPRSS2-ERG translocation during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A27.