Abstract
BackgroundTOP2A encodes for topoisomerase IIα, a nuclear enzyme that controls DNA topological structure and cell cycle progression. This enzyme is a marker of cell proliferation in normal and neoplastic tissues; however, little information is available about its expression in prostate cancer (PCa).MethodsImmunohistochemistry (IHC) was automated using mouse monoclonal antibody against TOP2A (clone SWT3D1; DAKO, Carpenteria, CA, USA) at dilution 1:800 and Flex Plus detection system in autostainer 48Ultra (DAKO). FISH was performed using TOP2A (17q21)/ CEP17 probe kit (Kreateck Biotechnology, San Diego, CA, USA). Biochemical and pathological data from 193 patients with PCa were retrieved for the analysis, whose significance was considered when p < 0.05. Also, fractal analysis was performed in a subset of 20 randomly selected cases.ResultsTOP2A protein expression correlated with higher Gleason scores and higher levels of preoperative PSA (p = 0.018 and p = 0.011). Patients with higher levels of TOP2A presented shorter biochemical recurrence-free survival (BRFS) (p = 0.001). In multivariate analysis, we found that TOP2A remained an independent prognostic factor of BRFS, with a relative risk of 1.98 (p = 0.001; 95% CI, 1.338–2.93); thus, cases that expressed high levels of this enzyme had a shorter BRFS compared with TOP2A-negative or TOP2A-low cases. No alterations in TOP2A gene status nor correlation between FISH and IHC results were observed. Concerning fractal analysis, patients who expressed higher levels of TOP2A have angiolymphatic invasion and presented higher Gleason scores (p = 0.033 and p = 0.025, respectively). Also, patients with higher expression of TOP2A presented shorter BRFS (p = 0.001).ConclusionsThis is the first study to perform TOP2A protein and gene digital assessment and fractal analysis in association with BRFS in a large series of PCa. Also, we show that TOP2A gene copy number alterations are not observed in this type of tumor. So, higher protein expression of TOP2A is not related to gene amplification in PCa. Furthermore, TOP2A protein assessment has prognostic importance and, due to its relation with poor outcome, TOP2A IHC evaluation in the biopsy can represent an important tool for selecting the most suitable surgical and clinical approach for patients with PCa.
Highlights
Two homologous but distinct isoforms of type II human topoisomerases have been identified: the 1531 amino acid 170 kDa DNA topoisomerase IIα (TOP2A) and the 1621 amino acid 180 kDa DNA topoisomerase IIβ (TOP2B) encoded by the highly related TOP2A and TOP2B genes, respectively [1,2]
Little information is available about TOP2A expression in prostate carcinoma [6]
In the present study we showed the prognostic importance of TOP2A in prostate cancer (PCa) by correlating immunohistochemical (IHC) and fluorescent in situ hybridization (FISH) with well-established prognostic values in PCa and with patients’ biochemical and pathological data and biochemical recurrence-free survival (BRFS)
Summary
Two homologous but distinct isoforms of type II human topoisomerases have been identified: the 1531 amino acid 170 kDa DNA topoisomerase IIα (TOP2A) and the 1621 amino acid 180 kDa DNA topoisomerase IIβ (TOP2B) encoded by the highly related TOP2A and TOP2B genes, respectively [1,2]. TOP2A is reported to be a sensitive and specific marker of actively proliferating cells (in the late S, G2 and M-phases of the cell cycle), which suggests the importance of its investigation in cancer [1]. Prostate cancer (PCa) alone accounts for 28% (217,730) of incident cases in men [3]. This disease exhibits considerable variability in clinical behavior [4]. TOP2A encodes for topoisomerase IIα, a nuclear enzyme that controls DNA topological structure and cell cycle progression. This enzyme is a marker of cell proliferation in normal and neoplastic tissues; little information is available about its expression in prostate cancer (PCa)
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