biostudies-literatureUnknown10(1)Rochel NThe upregulation of PPAR?/RXR? transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPAR?-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? overexpression and to recurrent activating point mutations of RXR?. Here, we report recurrent mutations of PPAR? that also activate the PPAR?/RXR? pathway, conferring PPAR?-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? 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 PPAR?/RXR? pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.Nature communications253https://www.ebi.ac.uk/biostudies/studies/S-EPMC6335423biostudies-literatureRecurrent activating mutations of PPAR? associated with luminal bladder tumors.PMC6335423Dejaegere AHernandez OAKrucker CBadawy KANeuzillet YLang HZhang RRadvanyi FKamoun ADufour FRochel NZita WAllory YRebouissou SCianferani SOsz JGuyon EVanthong SBernard-Pierrot IPeluso-Iltis CMassfelder THeckler-Beji SStote RHBourguet Mde Reynies ABeraud CCoutos-Thevenot LfalseRecurrent activating mutations of PPAR? associated with luminal bladder tumors.The upregulation of PPAR?/RXR? transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPAR?-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? overexpression and to recurrent activating point mutations of RXR?. Here, we report recurrent mutations of PPAR? that also activate the PPAR?/RXR? pathway, conferring PPAR?-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? 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 PPAR?/RXR? pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.2019-01-01T00:00:00Z2019 Jan2020-11-19T17:12:03Z2019-03-26T22:38:09ZS-EPMC63354233065155510.1038/s41467-018-08157-y