Prognostic value of mitotic checkpoint protein BUB3, cyclin B1, and pituitary tumor-transforming 1 expression in prostate cancer

Elin Ersvær,Håvard E Danielsen,Marco Novelli,Manohar Pradhan,Tarjei S Hveem,Wanja Kildal,Hanne A Askautrud,Håkon Wæhre,Ljiljana Vlatkovic,Knut Liestøl,Karolina Cyll,Andreas Kleppe

doi:10.1038/s41379-019-0418-2

Abstract

The mitotic checkpoint protein BUB3, cyclin B1 (CCNB1) and pituitary tumor-transforming 1 (PTTG1) regulates cell division, and are sparsely studied in prostate cancer. Deregulation of these genes can lead to genomic instability, a characteristic of more aggressive tumors. We aimed to determine the expression levels of BUB3, CCNB1, and PTTG1 as potential prognostic markers of recurrence after radical prostatectomy. Protein levels were determined by immunohistochemistry on three formalin-fixed paraffin-embedded tissue sections from each of the 253 patients treated with radical prostatectomy. Immunohistochemistry scores were obtained by automated image analysis for CCNB1 and PTTG1. Recurrence, defined as locoregional recurrence, distant metastasis or death from prostate cancer, was used as endpoint for survival analysis. Tumors having both positive and negative tumor areas for cytoplasmic BUB3 (30%), CCNB1 (28%), or PTTG1 (35%) were considered heterogeneous. Patients with ≥1 positive tumor area had significantly increased risk of disease recurrence in univariable analysis compared with patients where all tumor areas were negative for cytoplasmic BUB3 (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.41–3.36), CCNB1 (HR = 2.98, 95% CI 1.93–4.61) and PTTG1 (HR = 1.91, 95% CI 1.23–2.97). Combining the scores of cytoplasmic BUB3 and CCNB1 improved risk stratification when integrated with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score (difference in concordance index = 0.024, 95% CI 0.001–0.05). In analysis of multiple tumor areas, prognostic value was observed for cytoplasmic BUB3, CCNB1, and PTTG1.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Intra-tumor heterogeneity is common in prostate cancer, and may to some extent explain the difficulties in establishing useful molecular markers for this disease [1]
Intra-tumor heterogeneity is a beneficial trait for cancer progression and it likely develops due to genomic instability [2], which can be induced by defects in the mechanisms that regulate mitosis
As better risk stratification of patients with prostate cancer is needed [9], we aimed to investigate whether the expression of BUB3, cyclin B1 (CCNB1) and pituitary tumor-transforming 1 (PTTG1) could independently predict recurrence after radical prostatectomy

Summary

Introduction

Intra-tumor heterogeneity is a beneficial trait for cancer progression and it likely develops due to genomic instability [2], which can be induced by defects in the mechanisms that regulate mitosis. Correct attachment of the kinetochores inactivates the mitotic checkpoint complex, which facilitates the degradation of cyclin B1 (CCNB1) and pituitary tumor-transforming 1 (PTTG1), and determines exit from mitosis [3]. The expression of BUB3, CCNB1, and PTTG1 has been shown to correlate with tumor grade and prognosis in some cancers [6,7,8]. Their prognostic role in prostate cancer is unclear

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