Recurrent activating mutations of PPARγ associated with luminal bladder tumors

Natacha Rochel (), Clémentine Krucker, Laure Coutos-Thévenot, Judit Osz, Ruiyun Zhang, Elodie Guyon, Wayne Zita, Séverin Vanthong, Oscar Alba Hernandez, Maxime Bourguet, Kays Al Badawy, Florent Dufour, Carole Peluso-Iltis, Syrine Heckler-Beji, Annick Dejaegere, Aurélie Kamoun, Aurélien Reyniès, Yann Neuzillet, Sandra Rebouissou, Claire Béraud, Hervé Lang, Thierry Massfelder, Yves Allory, Sarah Cianférani, Roland H. Stote, François Radvanyi and Isabelle Bernard-Pierrot ()
Additional contact information
Natacha Rochel: UMR7104/Université de Strasbourg
Clémentine Krucker: Equipe Labellisée Ligue contre le Cancer
Laure Coutos-Thévenot: Equipe Labellisée Ligue contre le Cancer
Judit Osz: UMR7104/Université de Strasbourg
Ruiyun Zhang: Equipe Labellisée Ligue contre le Cancer
Elodie Guyon: Equipe Labellisée Ligue contre le Cancer
Wayne Zita: UMR7104/Université de Strasbourg
Séverin Vanthong: UMR7104/Université de Strasbourg
Oscar Alba Hernandez: IPHC UMR 7178
Maxime Bourguet: IPHC UMR 7178
Kays Al Badawy: UMR7104/Université de Strasbourg
Florent Dufour: Equipe Labellisée Ligue contre le Cancer
Carole Peluso-Iltis: UMR7104/Université de Strasbourg
Syrine Heckler-Beji: UMR7104/Université de Strasbourg
Annick Dejaegere: UMR7104/Université de Strasbourg
Aurélie Kamoun: Programme Cartes d’Identité des Tumeurs (CIT)
Aurélien Reyniès: Programme Cartes d’Identité des Tumeurs (CIT)
Yann Neuzillet: Equipe Labellisée Ligue contre le Cancer
Sandra Rebouissou: Equipe Labellisée Ligue contre le Cancer
Claire Béraud: School of Medicine
Hervé Lang: Hôpitaux Universitaires de Strasbourg
Thierry Massfelder: Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Yves Allory: Equipe Labellisée Ligue contre le Cancer
Sarah Cianférani: IPHC UMR 7178
Roland H. Stote: UMR7104/Université de Strasbourg
François Radvanyi: Equipe Labellisée Ligue contre le Cancer
Isabelle Bernard-Pierrot: Equipe Labellisée Ligue contre le Cancer

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-08157-y

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