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.
Original language | English |
---|---|
Pages (from-to) | 1549-1556 |
Number of pages | 8 |
Journal | Nature Medicine |
Volume | 26 |
Issue number | 10 |
DOIs | |
Publication status | Published - 1 Oct 2020 |
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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.
In: Nature Medicine, Vol. 26, No. 10, 01.10.2020, p. 1549-1556.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
AU - Bernard, Elsa
AU - Nannya, Yasuhito
AU - Hasserjian, Robert P.
AU - Devlin, Sean M.
AU - Tuechler, Heinz
AU - Medina-Martinez, Juan S.
AU - Yoshizato, Tetsuichi
AU - Shiozawa, Yusuke
AU - Saiki, Ryunosuke
AU - Malcovati, Luca
AU - Levine, Max F.
AU - Arango, Juan E.
AU - Zhou, Yangyu
AU - Solé, Francesc
AU - Cargo, Catherine A.
AU - Haase, Detlef
AU - Creignou, Maria
AU - Germing, Ulrich
AU - Zhang, Yanming
AU - Gundem, Gunes
AU - Sarian, Araxe
AU - van de Loosdrecht, Arjan A.
AU - Jädersten, Martin
AU - Tobiasson, Magnus
AU - Kosmider, Olivier
AU - Follo, Matilde Y.
AU - Thol, Felicitas
AU - Pinheiro, Ronald F.
AU - Santini, Valeria
AU - Kotsianidis, Ioannis
AU - Boultwood, Jacqueline
AU - Santos, Fabio P.S.
AU - Schanz, Julie
AU - Kasahara, Senji
AU - Ishikawa, Takayuki
AU - Tsurumi, Hisashi
AU - Takaori-Kondo, Akifumi
AU - Kiguchi, Toru
AU - Polprasert, Chantana
AU - Bennett, John M.
AU - Klimek, Virginia M.
AU - Savona, Michael R.
AU - Belickova, Monika
AU - Ganster, Christina
AU - Palomo, Laura
AU - Sanz, Guillermo
AU - Ades, Lionel
AU - Della Porta, Matteo Giovanni
AU - Smith, Alexandra G.
AU - Werner, Yesenia
AU - Patel, Minal
AU - Viale, Agnès
AU - Vanness, Katelynd
AU - Neuberg, Donna S.
AU - Stevenson, Kristen E.
AU - Menghrajani, Kamal
AU - Bolton, Kelly L.
AU - Fenaux, Pierre
AU - Pellagatti, Andrea
AU - Platzbecker, Uwe
AU - Heuser, Michael
AU - Valent, Peter
AU - Chiba, Shigeru
AU - Miyazaki, Yasushi
AU - Finelli, Carlo
AU - Voso, Maria Teresa
AU - Shih, Lee Yung
AU - Fontenay, Michaela
AU - Jansen, Joop H.
AU - Cervera, José
AU - Atsuta, Yoshiko
AU - Gattermann, Norbert
AU - Ebert, Benjamin L.
AU - Bejar, Rafael
AU - Greenberg, Peter L.
AU - Cazzola, Mario
AU - Hellström-Lindberg, Eva
AU - Ogawa, Seishi
AU - Papaemmanuil, Elli
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088857953&partnerID=8YFLogxK
U2 - 10.1038/s41591-020-1008-z
DO - 10.1038/s41591-020-1008-z
M3 - Article
C2 - 32747829
AN - SCOPUS:85088857953
VL - 26
SP - 1549
EP - 1556
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 10
ER -