Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

Carlos Fonseca-Alves,Fabio Marchi,Marcio Carvalho,Silvia Rogatto,Rolando Villacis,Simon Larsen,Sandra Linde,Renée Laufer-Amorim

doi:10.3390/ijms20071555

Abstract

Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of TP53, MDM2 and ZBTB4 were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as ATM, BRCA1, CDH1, MEN1 and TP53, were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The MDM2, TP53, and ZBTB4 copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer.

Highlights

Prostate cancer (PC) is the second most common cancer in men worldwide and its incidence is especially high in developed countries [1]
17 genes (ACTG1, AK1, AKT2, BRD2, CD4, CRYAA, FAM83H, GNB3, LOC403555, MIR221, MIR338, SCN2B, SGSH, TIMP1, TNNT2, TPI1, and USP11) were covered by Copy number alterations (CNAs) in both proliferative inflammatory atrophies (PIA), and more than 20% of PC cases (≥3 cases)
Our results revealed that PIA cases presented a small number of CNAs compared with PC

Summary

Introduction

Prostate cancer (PC) is the second most common cancer in men worldwide and its incidence is especially high in developed countries [1]. The dog is the only animal that naturally develops prostate cancer with aging [2,3]. By sharing the same environment, dogs have been considered a natural model for human cancer [4]. The canine disease usually displays a more aggressive behavior and is associated with a high metastatic rate and poor prognosis [3]. Canine PC commonly present loss of androgen receptor (AR), NKX3.1, and PTEN expression [10,11]. The expression levels of these three proteins are associated with the aggressive behavior of canine PC, and resembles the clinical features of human hormone-refractory PC [7]

Methods

Results

Discussion

Conclusion