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Abstract
Aim: A novel strategy for prostate cancer (PrCa) biomarker discovery is described. Materials & methods: In vitro perturbation biology, proteomics and Bayesian causal analysis identified biomarkers that were validated in in vitro models and clinical specimens. Results: Filamin-B (FLNB) and Keratin-19 were identified as biomarkers. Filamin-A (FLNA) was found to be causally linked to FLNB. Characterization of the biomarkers in a panel of cells revealed differential mRNA expression and regulation. Moreover, FLNA and FLNB were detected in the conditioned media of cells. Last, in patients without PrCa, FLNA and FLNB blood levels were positively correlated, while in patients with adenocarcinoma the relationship is dysregulated. Conclusion: These data support the strategy and the potential use of the biomarkers for PrCa.
Lay abstract The goal of this study was to use a novel strategy that combines biological outputs with Bayesian network learning to identify potential biomarkers for prostate cancer (PrCa). This methodology identified two proteins, filamin B and keratin-19, as potential biomarkers for PrCa. The network map also identified a direct linkage between filamin B and filamin A, which is a protein that has previously been identified as playing a role in PrCa etiology. The identified proteins were then validated by examining their levels in a panel of PrCa cell lines and in human plasma samples.
Acknowledgements
The authors would like to thank E Diamandis, E Klein, S Shrivastava and A Dobi for their critical review of the manuscript and P Tekumalla and E Grund for assisting with preparation.
Author contributions
NR Narain, AR Diers, A Dalvi, W Wu, VR Akmaev, S Gesta, VK Vishnudas and R Sarangarajan conceived and designed the experiments. AR Diers, S Lao, JY Chan, S Schofield, J Andreazi, R Ouro-Djobo, JJ Jimenez, T Friss, N Tanna, S Wang, D Bunch, Y Sun, K Thapa, S Gesta and LO Rodrigues acquired, analyzed and/or interpreted the data. NR Narain, AR Diers, K Thapa, S Gesta, VK Vishnudas and R Sarangarajan drafted and revised the manuscript critically for important intellectual content. All authors approved the final version to be published.
Financial & competing interests disclosure
Funding for all components of this research study was provided by BERG, LLC. JJ Jimenez is a paid advisor for BERG, LLC and has stock options in the company. S Wang and D Bunch are paid advisors for BERG, LLC. S Wang has received grants from Roche Diagnostics. All other authors listed are current or previous employees of BERG, LLC and have stock options. NR Narain is co-founder of BERG, LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.