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

Oncotarget. 2017 Jul 18;8(29):47595-47606. doi: 10.18632/oncotarget.17394.

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 naïve 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.

Keywords: FOXM1; KI67; muscle invasive bladder cancer; subclassification; survival prediction.

MeSH terms

  • Biomarkers
  • Cluster Analysis
  • Cohort Studies
  • Female
  • Forkhead Box Protein M1 / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Prognosis
  • Proportional Hazards Models
  • Risk Factors
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / mortality*
  • Urinary Bladder Neoplasms / pathology
  • Urologic Neoplasms / genetics*
  • Urologic Neoplasms / mortality*
  • Urologic Neoplasms / pathology

Substances

  • Biomarkers
  • Forkhead Box Protein M1