Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

// Matti Annala 1,2,* , Kati Kivinummi 1,2,* , Joonas Tuominen 1,3 , Serdar Karakurt 1,3 , Kirsi Granberg 1,2 , Leena Latonen 1,3 , Antti Ylipää 1,2 , Liisa Sjöblom 1,3 , Pekka Ruusuvuori 1,2 , Outi Saramäki 1,3 , Kirsi M. Kaukoniemi 1,3 , Olli Yli-Harja 2 , Robert L. Vessella 4 , Teuvo L.J. Tammela 5 , Wei Zhang 6 , Tapio Visakorpi 1,3 and Matti Nykter 1,2 1 Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland 2 Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland 3 Fimlab Laboratories, Tampere University Hospital, Tampere, Finland 4 Department of Urology, University of Washington, Seattle, WA, USA 5 Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland 6 Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA * These authors contributed equally to this work Correspondence: Matti Nykter, email: // Tapio Visakorpi, email: // Keywords : prostate cancer, sequencing, fusion gene, SKIL Received : October 27, 2014 Accepted : January 15, 2015 Published : January 31, 2015 Abstract Prostate cancer is the third most common cause of male cancer death in developed countries, and one of the most comprehensively characterized human cancers. Roughly 60% of prostate cancers harbor gene fusions that juxtapose ETS-family transcription factors with androgen regulated promoters. A second subtype, characterized by SPINK1 overexpression, accounts for 15% of prostate cancers. Here we report the discovery of a new prostate cancer subtype characterized by rearrangements juxtaposing the SMAD inhibitor SKIL with androgen regulated promoters, leading to increased SKIL expression. SKIL fusions were found in 6 of 540 (1.1%) prostate cancers and 1 of 27 (3.7%) cell lines and xenografts. 6 of 7 SKIL -positive cancers were negative for ETS overexpression, suggesting mutual exclusivity with ETS fusions. SKIL knockdown led to growth arrest in PC-3 and LNCaP cell line models of prostate cancer, and its overexpression led to increased invasiveness in RWPE-1 cells. The role of SKIL as a prostate cancer oncogene lends support to recent studies on the role of TGF-β signaling as a rate-limiting step in prostate cancer progression. Our findings highlight SKIL as an oncogene and potential therapeutic target in 1-2% of prostate cancers, amounting to an estimated 10,000 cancer diagnoses per year worldwide.