Recurrent activating mutations of PPARγ associated with luminal bladder tumors

Nat Commun. 2019 Jan 16;10(1):253. doi: 10.1038/s41467-018-08157-y.


The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cohort Studies
  • Crystallography, X-Ray
  • Female
  • Gain of Function Mutation
  • HEK293 Cells
  • Humans
  • Male
  • Molecular Dynamics Simulation
  • PPAR gamma / chemistry
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • Protein Interaction Domains and Motifs / genetics
  • Retinoid X Receptor alpha / genetics*
  • Retinoid X Receptor alpha / metabolism
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • Structure-Activity Relationship
  • Urinary Bladder / pathology
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology


  • PPAR gamma
  • PPARG protein, human
  • Retinoid X Receptor alpha