Recurrent activating mutations of PPARγ associated with luminal bladder tumors View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-01-16

AUTHORS

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 de Reyniès, Yann Neuzillet, Sandra Rebouissou, Claire Béraud, Hervé Lang, Thierry Massfelder, Yves Allory, Sarah Cianférani, Roland H. Stote, François Radvanyi, Isabelle Bernard-Pierrot

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. More... »

PAGES

253

References to SciGraph publications

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    10

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-08157-y

    DOI

    http://dx.doi.org/10.1038/s41467-018-08157-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111348243

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30651555


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