Recurrent activating mutations of PPARγ associated with luminal bladder tumors

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