J R Gsponer1, M Braun2, V J Scheble3, T Zellweger4, A Bachmann5, S Perner2, T Vlajnic1, M Srivastava6, S H Tan7, A Dobi7, I A Sesterhenn8, S Srivastava7, L Bubendorf1, C Ruiz1. 1. Institute for Pathology, University Hospital Basel, University of Basel, Basel, Switzerland. 2. Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany. 3. Institute of Pathology, Comprehensive Cancer Center, University Hospital Tuebingen, Tuebingen, Germany. 4. Division of Urology, St Claraspital, Basel, Switzerland. 5. Department of Urology, University Hospital Basel, University of Basel, Basel, Switzerland. 6. Department of Anatomy, Physiology, and Genetics, and Institute for Molecular Medicine, Uniformed Services University of the Health Sciences, School of Medicine, Bethesda, MD, USA. 7. Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 8. Joint Pathology Center, Silver Spring, MD, USA.
Abstract
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.
BACKGROUND: Approximately half of the prostate carcinomasare 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.
Authors: David S Rickman; Ying-Bei Chen; Samprit Banerjee; Yihang Pan; Jindan Yu; Terry Vuong; Sven Perner; Christopher J Lafargue; Kirsten D Mertz; Sunita R Setlur; Kanishka Sircar; Arul M Chinnaiyan; Tarek A Bismar; Mark A Rubin; Francesca Demichelis Journal: Neoplasia Date: 2010-12 Impact factor: 5.715
Authors: Kyung Park; Scott A Tomlins; Kumaran M Mudaliar; Ya-Lin Chiu; Raquel Esgueva; Rohit Mehra; Khalid Suleman; Sooryanarayana Varambally; John C Brenner; Theresa MacDonald; Abhishek Srivastava; Ashutosh K Tewari; Ubaradka Sathyanarayana; Dea Nagy; Gary Pestano; Lakshmi P Kunju; Francesca Demichelis; Arul M Chinnaiyan; Mark A Rubin Journal: Neoplasia Date: 2010-07 Impact factor: 5.715
Authors: Karin G Hermans; Ronald van Marion; Herman van Dekken; Guido Jenster; Wytske M van Weerden; Jan Trapman Journal: Cancer Res Date: 2006-11-15 Impact factor: 12.701
Authors: Elahe A Mostaghel; Linda Geng; Ilona Holcomb; Ilsa M Coleman; Jared Lucas; Lawrence D True; Peter S Nelson Journal: Cancer Res Date: 2010-02-02 Impact factor: 12.701
Authors: Scott A Tomlins; Anders Bjartell; Arul M Chinnaiyan; Guido Jenster; Robert K Nam; Mark A Rubin; Jack A Schalken Journal: Eur Urol Date: 2009-04-24 Impact factor: 20.096
Authors: Rohit Mehra; Scott A Tomlins; Jianjun Yu; Xuhong Cao; Lei Wang; Anjana Menon; Mark A Rubin; Kenneth J Pienta; Rajal B Shah; Arul M Chinnaiyan Journal: Cancer Res Date: 2008-05-15 Impact factor: 12.701
Authors: B Furusato; S-H Tan; D Young; A Dobi; C Sun; A A Mohamed; R Thangapazham; Y Chen; G McMaster; T Sreenath; G Petrovics; D G McLeod; S Srivastava; I A Sesterhenn Journal: Prostate Cancer Prostatic Dis Date: 2010-06-29 Impact factor: 5.554
Authors: Cindy Ke Zhou; Denise Young; Edward D Yeboah; Sally B Coburn; Yao Tettey; Richard B Biritwum; Andrew A Adjei; Evelyn Tay; Shelley Niwa; Ann Truelove; Judith Welsh; James E Mensah; Robert N Hoover; Isabell A Sesterhenn; Ann W Hsing; Shiv Srivastava; Michael B Cook Journal: Am J Epidemiol Date: 2017-12-15 Impact factor: 4.897
Authors: D Ryan Ormond; B K Kleinschmidt-DeMasters; Daniel Cavalcante; Elizabeth E Smith; Scott D Cramer; M Scott Lucia Journal: J Neurooncol Date: 2019-01-17 Impact factor: 4.130
Authors: Miriam S Butler; Mani Roshan-Moniri; Michael Hsing; Desmond Lau; Ari Kim; Paul Yen; Marta Mroczek; Mannan Nouri; Scott Lien; Peter Axerio-Cilies; Kush Dalal; Clement Yau; Fariba Ghaidi; Yubin Guo; Takeshi Yamazaki; Sam Lawn; Martin E Gleave; Cheryl Y Gregory-Evans; Lawrence P McIntosh; Michael E Cox; Paul S Rennie; Artem Cherkasov Journal: Oncotarget Date: 2017-06-27
Authors: Mark Rezk; Ashish Chandra; Daniel Addis; Henrik Møller; Mina Youssef; Prokar Dasgupta; Hide Yamamoto Journal: BMJ Open Date: 2019-03-08 Impact factor: 2.692