Recurrent activating mutations of PPARγ associated with luminal bladder tumors

The upregulation of PPARgamma/RXRalpha transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARgamma-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 PPARgamma overexpression and to recurrent activating point mutations of RXRalpha. Here, we report recurrent mutations of PPARgamma that also activate the PPARgamma/RXRalpha pathway, conferring PPARgamma-dependency and supporting a crucial role of PPARgamma 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 PPARgamma 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 PPARgamma/RXRalpha pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.