To fully understand the output of alterations in cancer genomes and transcriptomes, we need to know how these aberrations are translated into the functional protein units in cells. We assessed proteomic changes during disease formation and progression in prostate cancer by performing high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC), and castration-resistant prostate cancer (CRPC). With SWATH-MS quantitation-based proteomics we found that each of these sample groups show a distinct protein profile. By integrative analysis of this mass spectrometry dataset with genetic, epigenetic, and transcriptional data from the same samples, we show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. From our analysis, we have identified sets of novel expression changes occurring primarily at the protein level, in addition to identification of several miRNA-target correlations present at protein but not at mRNA level. We find novel expression changes in previously unrecognized pathways in prostate cancer that are likely to affect disease development and progression. For example, we identify two metabolic shifts in the citric acid cycle (TCA cycle), one occurring during primary cancer development and the second during castration resistance, having implications on drug targeting against cancer metabolism. Our proteogenomic analysis of prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression, reveals new disease mechanisms, and significantly extends understanding of prostate cancer biology.
Citation Format: Leena Latonen, Ebrahim Afyounian, Antti Jylhä, Janika Nättinen, Ulla Aapola, Matti Annala, Kati Kivinummi, Teuvo Tammela, Roger W. Beuerman, Hannu Uusitalo, Matti Nykter, Tapio Visakorpi. Integrative analysis of the proteome in primary and advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A020.