ProstaMine: a bioinformatics tool for identifying subtype-specific co-alterations associated with aggressiveness in prostate cancer

Michael V Orman; Varsha Sreekanth; Teemu D Laajala; Scott D Cramer; James C Costello

doi:10.3389/fphar.2024.1360352

ProstaMine: a bioinformatics tool for identifying subtype-specific co-alterations associated with aggressiveness in prostate cancer

Front Pharmacol. 2024 May 1:15:1360352. doi: 10.3389/fphar.2024.1360352. eCollection 2024.

Authors

Michael V Orman¹, Varsha Sreekanth¹, Teemu D Laajala^{1

2}, Scott D Cramer^{1

3}, James C Costello^{1

3}

Affiliations

¹ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
² Department of Mathematics and Statistics, University of Turku, Turku, Finland.
³ University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

Abstract

Background: Prostate cancer is a leading cause of cancer-related deaths among men, marked by heterogeneous clinical and molecular characteristics. The complexity of the molecular landscape necessitates tools for identifying multi-gene co-alteration patterns that are associated with aggressive disease. The identification of such gene sets will allow for deeper characterization of the processes underlying prostate cancer progression and potentially lead to novel strategies for treatment.

Methods: We developed ProstaMine to systematically identify co-alterations associated with aggressiveness in prostate cancer molecular subtypes defined by high-fidelity alterations in primary prostate cancer. ProstaMine integrates genomic, transcriptomic, and clinical data from five primary and one metastatic prostate cancer cohorts to prioritize co-alterations enriched in metastatic disease and associated with disease progression.

Results: Integrated analysis of primary tumors defined a set of 17 prostate cancer alterations associated with aggressive characteristics. We applied ProstaMine to NKX3-1-loss and RB1-loss tumors and identified subtype-specific co-alterations associated with metastasis and biochemical relapse in these molecular subtypes. In NKX3-1-loss prostate cancer, ProstaMine identified novel subtype-specific co-alterations known to regulate prostate cancer signaling pathways including MAPK, NF-kB, p53, PI3K, and Sonic hedgehog. In RB1-loss prostate cancer, ProstaMine identified novel subtype-specific co-alterations involved in p53, STAT6, and MHC class I antigen presentation. Co-alterations impacting autophagy were noted in both molecular subtypes.

Conclusion: ProstaMine is a method to systematically identify novel subtype-specific co-alterations associated with aggressive characteristics in prostate cancer. The results from ProstaMine provide insights into potential subtype-specific mechanisms of prostate cancer progression which can be formed into testable experimental hypotheses. ProstaMine is publicly available at: https://bioinformatics.cuanschutz.edu/prostamine.

Keywords: NKX3-1; RB1; bioinformatics analysis; data mining algorithm; molecular subtypes; prostate cancer.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was generously supported by the Anschutz Foundation and CA241647 to JC, CA231978 to JC and SC, CA262279 to SC, and FICAN Cancer Researcher by the Finnish Cancer Institute and Finnish Cultural Foundation to TL. This work used resources from the Biostatistics and Bioinformatics Shared Resource supported by the University of Colorado Cancer Center, an NCI designated Comprehensive Cancer Center (CA046934).