Early mRNA Expression of Neuroendocrine Differentiation Signals Predicts Recurrence After Radical Prostatectomy: A Transcriptomic Analysis

Panagiotis J Vlachostergios; Athanasios Karathanasis; Christos N Papandreou; Vassilios Tzortzis

doi:10.14740/wjon1423

Early mRNA Expression of Neuroendocrine Differentiation Signals Predicts Recurrence After Radical Prostatectomy: A Transcriptomic Analysis

World J Oncol. 2021 Dec;12(6):232-239. doi: 10.14740/wjon1423. Epub 2021 Dec 8.

Authors

Panagiotis J Vlachostergios¹, Athanasios Karathanasis², Christos N Papandreou³, Vassilios Tzortzis²

Affiliations

¹ Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
² Department of Urology, University of Thessaly School of Health Sciences Faculty of Medicine, University Hospital of Larissa, Larissa 41100, Greece.
³ Department of Medical Oncology, Faculty of Medicine Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Thessaloniki 54124, Greece.

Abstract

Background: Neuroendocrine differentiation (NED) of prostate cancer (PC) is a process that often occurs under evolutionary pressure from pharmacologic blockade of androgen receptor signaling at advanced stages of the disease. Identifying a subset of early PC that has a higher likelihood to evolve into this entity is key for developing therapeutic strategies that could more effectively target this phenotype. This study aimed to assess the prognostic relevance of mRNA expression of major players involved in NED of primary prostate tumors.

Methods: RNA sequencing data from 122 patients with localized PC were analyzed. Transcript levels of key genes involved in NED, with a focus on endothelin axis and nuclear factor kappa B (NF-κB), were assessed and were correlated with time to prostate specific antigen (PSA) recurrence. Copy number alteration of tumor suppressor genes and gene expression of additional signals hallmarking NED was compared between altered and unaltered groups, including lineage determining transcription factors, transcriptional repressors, cell cycle and epigenetic regulators.

Results: The presence of altered mRNA expression using a z-score threshold of 2 in NFKB1, RELA, EDN1, EDNRA, and EDNRB genes was associated with a higher Gleason score (P < 0.001) and a shorter time to biochemical recurrence (BCR) (P = 0.029). There was a significant direct correlation between NFKB1 and RELA (P < 0.001), NFKB1 and EDNRA (P < 0.001), NFKB1 and EDNRB (P < 0.001), EDNRA and EDNRB expression (P < 0.001). ASCL1 (q < 0.001), ONECUT2 (q < 0.001), DLL3 (q = 0.019), AURKA (q = 0.013), AURKB (q = 0.014), PLK1 (q < 0.001), and EZH2 (q < 0.001) were enriched in patients with tumors harboring alterations in endothelin axis and NF-κB subunit genes whereas REST was downregulated (q < 0.001).

Conclusions: This analysis suggests that altered mRNA expression of NF-κB and endothelin axis genes in early PC is not only a harbinger of a more aggressive clinical course but is also associated with aberrant gene expression of several transcription factors, transcriptional repressors, cell cycle and epigenetic regulators that are directly involved in NED, in line with their biological roles. This may have implications for closer follow-up and potential use of targeted therapeutic approaches postoperatively in the adjuvant setting to improve outcomes of these patients.

Keywords: Endothelin; Neuroendocrine differentiation; Nuclear factor kappa B; PSA recurrence; Prostate cancer; RNA sequencing; Radical prostatectomy; mRNA expression.