Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer

Eur Urol. 2016 Oct;70(4):611-620. doi: 10.1016/j.eururo.2016.02.056. Epub 2016 Mar 15.


Background: Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival.

Objective: To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior.

Design, setting, and participants: We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling.

Outcome measurements and statistical analysis: The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays.

Results and limitations: We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor γ and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation.

Conclusions: Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes.

Patient summary: Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.

Keywords: Expression profile; Micropapillary bladder cancer; Molecular signature; Prognosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • Carcinoma, Transitional Cell / drug therapy
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / pathology*
  • Carrier Proteins / genetics
  • DNA Helicases / genetics
  • Down-Regulation
  • GATA3 Transcription Factor / genetics
  • Humans
  • Hyaluronan Receptors / genetics
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Keratin-14 / genetics
  • MicroRNAs / genetics
  • PPAR gamma / genetics
  • Proportional Hazards Models
  • RNA, Messenger / analysis*
  • Retrospective Studies
  • Survival Rate
  • Tissue Array Analysis
  • Transcription Factors / genetics
  • Transcriptome*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology*
  • Uroplakin II / genetics
  • Whole Genome Sequencing


  • CD44 protein, human
  • Carrier Proteins
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Hyaluronan Receptors
  • KRT14 protein, human
  • Keratin-14
  • MIRN296 microRNA, human
  • MicroRNAs
  • PPAR gamma
  • RNA, Messenger
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • UPK2 protein, human
  • Uroplakin II
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL1 protein, human