Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Abstract

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.

Metadata

Item Type:	Article
Authors/Creators:	Bernard, Elsa Nannya, Yasuhito Hasserjian, Robert P. Devlin, Sean M. Tuechler, Heinz Medina-Martinez, Juan S. Yoshizato, Tetsuichi Shiozawa, Yusuke Saiki, Ryunosuke Malcovati, Luca Levine, Max F. Arango, Juan E. Zhou, Yangyu Solé, Francesc Cargo, Catherine A. Haase, Detlef Creignou, Maria Germing, Ulrich Zhang, Yanming Gundem, Gunes Sarian, Araxe van de Loosdrecht, Arjan A. Jädersten, Martin Tobiasson, Magnus Kosmider, Olivier Follo, Matilde Y. Thol, Felicitas Pinheiro, Ronald F. Santini, Valeria Kotsianidis, Ioannis Boultwood, Jacqueline Santos, Fabio P. S. Schanz, Julie Kasahara, Senji Ishikawa, Takayuki Tsurumi, Hisashi Takaori-Kondo, Akifumi Kiguchi, Toru Polprasert, Chantana Bennett, John M. Klimek, Virginia M. Savona, Michael R. Belickova, Monika Ganster, Christina Palomo, Laura Sanz, Guillermo Ades, Lionel Della Porta, Matteo Giovanni Smith, Alexandra G. https://orcid.org/0000-0002-1111-966X Werner, Yesenia Patel, Minal Viale, Agnès Vanness, Katelynd Neuberg, Donna S. Stevenson, Kristen E. Menghrajani, Kamal Bolton, Kelly L. Fenaux, Pierre Pellagatti, Andrea Platzbecker, Uwe Heuser, Michael Valent, Peter Chiba, Shigeru Miyazaki, Yasushi Finelli, Carlo Voso, Maria Teresa Shih, Lee-Yung Fontenay, Michaela Jansen, Joop H. Cervera, José Atsuta, Yoshiko Gattermann, Norbert Ebert, Benjamin L. Bejar, Rafael Greenberg, Peter L. Cazzola, Mario Hellström-Lindberg, Eva Ogawa, Seishi Papaemmanuil, Elli
Copyright, Publisher and Additional Information:	© 2020 Springer Nature Limited. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Dates:	Accepted: 7 July 2020 Published (online): 3 August 2020 Published: October 2020
Institution:	The University of York
Academic Units:	The University of York > Faculty of Sciences (York) > Health Sciences (York)
Depositing User:	Pure (York)
Date Deposited:	04 Aug 2020 13:10
Last Modified:	02 Apr 2025 23:19
Published Version:	https://doi.org/10.1038/s41591-020-1008-z
Status:	Published
Refereed:	Yes
Identification Number:	10.1038/s41591-020-1008-z
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:164025

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Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

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