| Literature DB >> 32747829 |
Elsa Bernard1,2, Yasuhito Nannya3, Robert P Hasserjian4, Sean M Devlin5, Heinz Tuechler6, Juan S Medina-Martinez1,2, Tetsuichi Yoshizato3, Yusuke Shiozawa3, Ryunosuke Saiki3, Luca Malcovati7,8, Max F Levine1,2, Juan E Arango1,2, Yangyu Zhou1,2, Francesc Solé9, Catherine A Cargo10, Detlef Haase11, Maria Creignou12, Ulrich Germing13, Yanming Zhang14, Gunes Gundem1, Araxe Sarian2, Arjan A van de Loosdrecht15, Martin Jädersten12, Magnus Tobiasson12, Olivier Kosmider16, Matilde Y Follo17, Felicitas Thol18, Ronald F Pinheiro19, Valeria Santini20, Ioannis Kotsianidis21, Jacqueline Boultwood22, Fabio P S Santos23, Julie Schanz11, Senji Kasahara24, Takayuki Ishikawa25, Hisashi Tsurumi26, Akifumi Takaori-Kondo27, Toru Kiguchi28, Chantana Polprasert29, John M Bennett30, Virginia M Klimek31, Michael R Savona32, Monika Belickova33, Christina Ganster11, Laura Palomo9, Guillermo Sanz34,35, Lionel Ades36, Matteo Giovanni Della Porta37,38, Harold K Elias31, Alexandra G Smith39, Yesenia Werner1, Minal Patel2, Agnès Viale40, Katelynd Vanness40, Donna S Neuberg41, Kristen E Stevenson41, Kamal Menghrajani31, Kelly L Bolton31, Pierre Fenaux36, Andrea Pellagatti22, Uwe Platzbecker42, Michael Heuser18, Peter Valent43, Shigeru Chiba44, Yasushi Miyazaki45, Carlo Finelli46, Maria Teresa Voso47, Lee-Yung Shih48, Michaela Fontenay16, Joop H Jansen49, José Cervera50, Yoshiko Atsuta51, Norbert Gattermann13, Benjamin L Ebert52, Rafael Bejar53, Peter L Greenberg54, Mario Cazzola7,8, Eva Hellström-Lindberg12, Seishi Ogawa3, Elli Papaemmanuil55,56.
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.Entities:
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Year: 2020 PMID： 32747829 PMCID： PMC8381722 DOI： 10.1038/s41591-020-1008-z
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440