Abstract 4351: Identification of molecular signature associated with the castration-resistant prostate cancer (CRPC) development by next-generation sequencing (NGS)-based transcriptomic profiling

Abstract

Abstract Backgrounds: Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer produced by disease progression following surgical or pharmaceutical castration. The development process of CRPC becoming castrate resistant is unclear. The objective of this study is to identify a gene set and putative signaling pathway for mediating the development of CRPC. Methods: RNA-seq data was generated using 54 prostate samples [primary prostate cancer (PCa), CRPC, and benign prostatic hyperplasia (BPH)], among which 8 were paired samples of PCa and CRPC obtained from 4 patients. Diverse statistical methods, including a generalized linear model likelihood ratio test, were applied to identify the signature associated with CRPC development. The interconnectivity between genes in the signature was verified by Ingenuity Pathway Analysis TM. We also confirmed a relevance of the signature with experimental assays using prostate cancer cell lines. Results: Unsupervised hierarchical cluster analysis of RNA-seq data revealed a clear gene expression pattern of tumorigenesis in PCa with heterogeneous molecular characteristics of CRPC. Comparing paired cancer samples, 309 genes were differentially expressed between PCa and CRPC samples. We also tested unpaired sample groups (PCa vs. CRPC) and found that 182 genes had significantly differences of expression (a generalized linear model likelihood ratio test, P < 0.001, a 2-fold or greater relative difference). When comparing two gene sets, a total of 15 genes was common in both paired and unpaired CRPC groups. Among them, AR and SPINK1 were significantly increased in the CRPC than in the PCa groups. Gene network analyses and experimental assays of AR and SPINK1 revealed that CRPC development could be mediated by SPINK1-AR pathway. Conclusion: The molecular signature defined by activation of SPINK1-AR may be a genetic determinant of progression from PCa to CRPC. Note: This abstract was not presented at the meeting. Citation Format: Seon-Kyu Kim, Jeong-Hwan Kim, Pildu Jeong, Wun-Jae Kim, Yong Sung Kim, Seok-Joong Yun, Seon-Young Kim. Identification of molecular signature associated with the castration-resistant prostate cancer (CRPC) development by next-generation sequencing (NGS)-based transcriptomic profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4351. doi:10.1158/1538-7445.AM2015-4351