FOXM1 predicts overall and disease specific survival in muscle-invasive urothelial carcinoma and presents a differential expression between bladder cancer subtypes

// Sebastien Rinaldetti 1 , Ralph Markus Wirtz 2 , Thomas Stefan Worst 3 , Markus Eckstein 4 , Cleo Aaron Weiss 5 , Johannes Breyer 6 , Wolfgang Otto 6 , Christian Bolenz 7 , Arndt Hartmann 4 and Philipp Erben 3 1 Department of Hematology and Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany 2 Stratifyer Molecular Pathology GmbH, 50935 Koln, Germany 3 Department of Urology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany 4 Institute of Pathology, University Erlangen-Nuremberg, 91054 Erlangen, Germany 5 Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany 6 Department of Urology, University of Regensburg, 93053 Regensburg, Germany 7 Department of Urology, University of Ulm, 89075 Ulm, Germany Correspondence to: Sebastien Rinaldetti, email: sebastienrinal@hotmail.com Keywords: FOXM1, muscle invasive bladder cancer, KI67, subclassification, survival prediction Received: December 28, 2016     Accepted: April 10, 2017     Published: April 24, 2017 ABSTRACT Forkhead box M1 (FOXM1) is a late cell cycle gene that plays a crucial role in carcinogenesis and chemotherapeutic drug resistance. In this study, the impact of FOXM1 expression on patient outcome was investigated for the first time in formalin fixed and paraffin embedded (FFPE) samples of chemotherapy naive muscle-invasive bladder cancer (MIBC) patients. Expression analyses were performed on the Mannheim cohort (n=84) and validated on the independent Chungbuk cohort (n=61). In a Cox’ proportional hazards model, a distinct FOXM1 expression cut-off dividing both cohorts in a ‘high-risk’ and ‘low-risk’ group has been determined. Multivariate analyses showed that FOXM1 is an independent risk factor for outcome prediction superior to the TNM system. The FOXM1 ‘high-risk’ group had a 4- to 7-fold increased risk of death (p<0.03) and presented further an overexpression of MKI67. Recent studies showed that MIBCs can be subclassified in breast cancer-like subtypes: basal, luminal and p53-like. Here we demonstrated that FOXM1 was differentially expressed between MIBC subtypes concordant to its subtype specific expression in breast cancer. Since the proto-oncogene FOXM1 is known to play an important role in cisplatin resistance and to be a promising drug target, this study supports FOXM1 as a crucial biomarker in the personalization of MIBC therapy and urges prospective translational studies.