Transcriptomic features of primary prostate cancer and their prognostic relevance to castration-resistant prostate cancer
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Seok Joong Yun1,2,*, Seon-Kyu Kim3,*, Jayoung Kim4,5,6, Eun-Jong Cha7, Jang-Seong Kim8, Sun-Jin Kim9, Yun-Sok Ha10, Ye-Hwan Kim1, Pildu Jeong1, Ho Won Kang2, Jeong-Hwan Kim3, Jong-Lyul Park3, Young-Ki Choi11, Sung-Kwon Moon12, Yung-Hyun Choi13, Seon-Young Kim3,14 and Wun-Jae Kim1,2
1Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea
2Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
3Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
4Department of Surgery, Harvard Medical School, Boston, MA, USA
5Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
6Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
7Department of Biomedical Engineering, Chungbuk National University College of Medicine, Cheongju, Korea
8Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
9R&D Center, Hanmi Pharm. Co. Ltd., Hwaseong-si, Korea
10Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea
11Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea
12School of Food Science and Technology, Chung-Ang University, Anseong, Korea
13Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan, Korea
14Department of Functional Genomics, University of Science and Technology, Daejeon, Korea
*These authors have contributed equally to this work
Wun-Jae Kim, email: firstname.lastname@example.org
Seon-Young Kim, email: email@example.com
Keywords: CRPC; disease progression; markers; prognosis; gene expression
Received: June 20, 2017 Accepted: August 27, 2017 Published: November 06, 2017
Although various mechanisms of castration-resistant prostate cancer (CRPC) have been discovered, reliable biomarkers for monitoring CRPC progression are lacking. We sought to identify molecules that predict the progression of advanced prostate cancer (AdvPC) into CRPC. The study used primary-site samples (N=45 for next-generation sequencing (NGS); N=243 for real-time polymerase chain reaction) from patients with prostate cancer (PC). Five public databases containing microarray data of AdvPC and CRPC samples were analyzed. The NGS data showed that each progression step in PC associated with distinct gene expression profiles. Androgen receptor (AR) associated with tumorigenesis, advanced progression, and progression into CRPC. Analysis of the paired and unpaired AdvPC and CRPC samples in the NGS cohort showed that 15 genes associated with progression into CRPC. This was validated by cohort-1 and public database analyses. Analysis of the third cohort with AdvPC showed that higher serine peptidase inhibitor, Kazal type 1 (SPINK1) and lower Sp8 transcription factor (SP8) expression associated with progression into CRPC (log-rank test, both P<0.05). Multivariate regression analysis showed that higher SPINK1 (Hazard Ratio (HR)=4.506, 95% confidence intervals (CI)=1.175–17.29, P=0.028) and lower SP8 (HR=0.199, 95% CI=0.063–0.632, P=0.006) expression independently predicted progression into CRPC. Gene network analysis showed that CRPC progression may be mediated through the AR-SPINK1 pathway by a HNF1A-based gene network. Taken together, our results suggest thatSPINK1 and SP8 may be useful for classifying patients with AdvPC who have a higher risk of progressing to CRPC.
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