An RNA-Seq-Based Framework for Characterizing Canine Prostate Cancer and Prioritizing Clinically Relevant Biomarker Candidate Genes.

Heike Thiemeyer,Ekkehard Schütz,Eva-Maria Packeiser,Jan Torben Schille,Hugo Murua Escobar,Ingo Nolte,Lisa K Harder,Bertram Brenig,Marion Hewicker-Trautwein,Leila Taher,Julia Beck

doi:10.3390/ijms222111481

Abstract

Prostate cancer (PCa) in dogs is a highly malignant disease akin to its human counterpart. In contrast to the situation in humans, multi-gene approaches facilitating risk stratification of canine PCa are barely established. The aims of this study were the characterization of the transcriptional landscape of canine PCa and the identification of diagnostic, prognostic and/or therapeutic biomarkers through a multi-step screening approach. RNA-Sequencing of ten malignant tissues and fine-needle aspirations (FNA), and 14 nonmalignant tissues and FNAs was performed to find differentially expressed genes (DEGs) and deregulated pathways. The 4098 observed DEGs were involved in 49 pathways. These 49 pathways could be grouped into five superpathways summarizing the hallmarks of canine PCa: (i) inflammatory response and cytokines; (ii) regulation of the immune system and cell death; (iii) cell surface and PI3K signaling; (iv) cell cycle; and (v) phagosome and autophagy. Among the highly deregulated, moderately to strongly expressed DEGs that were members of one or more superpathways, 169 DEGs were listed in relevant databases and/or the literature and included members of the PCa pathway, oncogenes, prostate-specific genes, and druggable genes. These genes are novel and promising candidate diagnostic, prognostic and/or therapeutic canine PCa biomarkers.

Highlights

Prostate cancer (PCa) in dogs can occur spontaneously, with aging dogs exhibiting higher incidence thereof than any other nonhuman species [1,2,3]
To the best of our knowledge, this is the first tissue- and biopsy-based study comparatively characterizing the transcriptional landscape of canine PCa samples and samples of nonmalignant origin
In addition to identifying five superpathways encapsulating the hallmarks of canine PCa, we provide a framework for prioritizing candidate canine PCa biomarkers for different purposes

Summary

Introduction

Prostate cancer (PCa) in dogs can occur spontaneously, with aging dogs exhibiting higher incidence thereof than any other nonhuman species [1,2,3]. With regard to the prostate-specific antigen (PSA, encoded by Kallikrein Related Peptidase 3 or KLK3), as commonly used blood serum biomarker in regular checkups for human PCa [21], no unambiguous canine ortholog has been identified for the human gene encoding PSA, i.e., KLK3 [22]. The canine prostate-specific arginine esterase (CPSE, encoded by KLK2), another member of the kallikrein family with striking similarities to human PSA [23], has been suggested as a blood serum marker for diagnosing benign prostatic hyperplasia [24]. Most canine PCa continues to be diagnosed at an advanced stage with limited therapeutic options [5,7]

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