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IRIS
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.
Bernard, E., Nannya, Y., Hasserjian, R.p., Devlin, S.m., Tuechler, H., Medina-Martinez, J.s., et al. (2020). Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. NATURE MEDICINE, 26(10), 1549-1556 [10.1038/s41591-020-1008-z].
Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
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;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
2020-01-01
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.
Alleles Cohort Studies DNA Copy Number Variations DNA Mutational Analysis Female Gene Frequency Genomic Instability Humans Loss of Heterozygosity Male Mutation Myelodysplastic Syndromes Phenotype Prognosis Survival Analysis Treatment Outcome Tumor Suppressor Protein p53
Bernard, E., Nannya, Y., Hasserjian, R.p., Devlin, S.m., Tuechler, H., Medina-Martinez, J.s., et al. (2020). Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. NATURE MEDICINE, 26(10), 1549-1556 [10.1038/s41591-020-1008-z].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/261816
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simulazione ASN
Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
La presente simulazione è stata realizzata sulla base delle specifiche raccolte sul tavolo ER del Focus Group IRIS coordinato dall’Università di Modena e Reggio Emilia e delle regole riportate nel DM 589/2018 e allegata Tabella A. Cineca, l’Università di Modena e Reggio Emilia e il Focus Group IRIS non si assumono alcuna responsabilità in merito all’uso che il diretto interessato o terzi faranno della simulazione. Si specifica inoltre che la simulazione contiene calcoli effettuati con dati e algoritmi di pubblico dominio e deve quindi essere considerata come un mero ausilio al calcolo svolgibile manualmente o con strumenti equivalenti.