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

Elsa Bernard; Yasuhito Nannya; Robert P. Hasserjian; Sean M. Devlin; Heinz Tuechler; Juan S. Medina-Martinez; Tetsuichi Yoshizato; Yusuke Shiozawa; Ryunosuke Saiki; Luca Malcovati; Max F. Levine; Juan E. Arango; Yangyu Zhou; Francesc Solé; Catherine A. Cargo; Detlef Haase; Maria Creignou; Ulrich Germing; Yanming Zhang; Gunes Gundem; Araxe Sarian; Arjan A. van de Loosdrecht; Martin Jädersten; Magnus Tobiasson; Olivier Kosmider; Matilde Y. Follo; Felicitas Thol; Ronald F. Pinheiro; Valeria Santini; Ioannis Kotsianidis; Jacqueline Boultwood; Fabio P.S. Santos; Julie Schanz; Senji Kasahara; Takayuki Ishikawa; Hisashi Tsurumi; Akifumi Takaori-Kondo; Toru Kiguchi; Chantana Polprasert; John M. Bennett; Virginia M. Klimek; Michael R. Savona; Monika Belickova; Christina Ganster; Laura Palomo; Guillermo Sanz; Lionel Ades; Matteo Giovanni Della Porta; Alexandra G. Smith; Yesenia Werner; Minal Patel; Agnès Viale; Katelynd Vanness; Donna S. Neuberg; Kristen E. Stevenson; Kamal Menghrajani; Kelly L. Bolton; Pierre Fenaux; Andrea Pellagatti; Uwe Platzbecker; Michael Heuser; Peter Valent; Shigeru Chiba; Yasushi Miyazaki; Carlo Finelli; Maria Teresa Voso; Lee Yung Shih; Michaela Fontenay; Joop H. Jansen; José Cervera; Yoshiko Atsuta; Norbert Gattermann; Benjamin L. Ebert; Rafael Bejar; Peter L. Greenberg; Mario Cazzola; Eva Hellström-Lindberg; Seishi Ogawa; Elli Papaemmanuil

doi:10.1038/s41591-020-1008-z

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

Elsa Bernard, Yasuhito Nannya, Robert P. Hasserjian, Sean M. Devlin, Heinz Tuechler, Juan S. Medina-Martinez, Tetsuichi Yoshizato, Yusuke Shiozawa, Ryunosuke Saiki, Luca Malcovati, Max F. Levine, Juan E. Arango, Yangyu Zhou, Francesc Solé, Catherine A. Cargo, Detlef Haase, Maria Creignou, Ulrich Germing, Yanming Zhang, Gunes GundemAraxe Sarian, Arjan A. van de Loosdrecht, Martin Jädersten, Magnus Tobiasson, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Ronald F. Pinheiro, Valeria Santini, Ioannis Kotsianidis, Jacqueline Boultwood, Fabio P.S. Santos, Julie Schanz, Senji Kasahara, Takayuki Ishikawa, Hisashi Tsurumi, Akifumi Takaori-Kondo, Toru Kiguchi, Chantana Polprasert, John M. Bennett, Virginia M. Klimek, Michael R. Savona, Monika Belickova, Christina Ganster, Laura Palomo, Guillermo Sanz, Lionel Ades, Matteo Giovanni Della Porta, Alexandra G. Smith, Yesenia Werner, Minal Patel, Agnès Viale, Katelynd Vanness, Donna S. Neuberg, Kristen E. Stevenson, Kamal Menghrajani, Kelly L. Bolton, Pierre Fenaux, Andrea Pellagatti, Uwe Platzbecker, Michael Heuser, Peter Valent, Shigeru Chiba, Yasushi Miyazaki, Carlo Finelli, Maria Teresa Voso, Lee Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Yoshiko Atsuta, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Peter L. Greenberg, Mario Cazzola, Eva Hellström-Lindberg, Seishi Ogawa, Elli Papaemmanuil^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer^1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease^3,4, rapid transformation to acute myeloid leukemia (AML)⁵, resistance to conventional therapies^6–8 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	https://doi.org/10.1038/s41591-020-1008-z
Publication status	Published - 1 Oct 2020

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Bernard, E., Nannya, Y., Hasserjian, R. P., Devlin, S. M., Tuechler, H., Medina-Martinez, J. S., Yoshizato, T., Shiozawa, Y., Saiki, R., Malcovati, L., Levine, M. F., Arango, J. E., Zhou, Y., Solé, F., Cargo, C. A., Haase, D., Creignou, M., Germing, U., Zhang, Y., ... Papaemmanuil, E. (2020). Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nature Medicine, 26(10), 1549-1556. https://doi.org/10.1038/s41591-020-1008-z

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. / Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. In: Nature Medicine. 2020 ; Vol. 26, No. 10. pp. 1549-1556.

@article{8b8ab41bd3c045afb932141f23d61cab,

title = "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.",

author = "Elsa Bernard and Yasuhito Nannya and Hasserjian, {Robert P.} and Devlin, {Sean M.} and Heinz Tuechler and Medina-Martinez, {Juan S.} and Tetsuichi Yoshizato and Yusuke Shiozawa and Ryunosuke Saiki and Luca Malcovati and Levine, {Max F.} and Arango, {Juan E.} and Yangyu Zhou and Francesc Sol{\'e} and Cargo, {Catherine A.} and Detlef Haase and Maria Creignou and Ulrich Germing and Yanming Zhang and Gunes Gundem and Araxe Sarian and {van de Loosdrecht}, {Arjan A.} and Martin J{\"a}dersten and Magnus Tobiasson and Olivier Kosmider and Follo, {Matilde Y.} and Felicitas Thol and Pinheiro, {Ronald F.} and Valeria Santini and Ioannis Kotsianidis and Jacqueline Boultwood and Santos, {Fabio P.S.} and Julie Schanz and Senji Kasahara and Takayuki Ishikawa and Hisashi Tsurumi and Akifumi Takaori-Kondo and Toru Kiguchi and Chantana Polprasert and Bennett, {John M.} and Klimek, {Virginia M.} and Savona, {Michael R.} and Monika Belickova and Christina Ganster and Laura Palomo and Guillermo Sanz and Lionel Ades and {Della Porta}, {Matteo Giovanni} and Smith, {Alexandra G.} and Yesenia Werner and Minal Patel and Agn{\`e}s Viale and Katelynd Vanness and Neuberg, {Donna S.} and Stevenson, {Kristen E.} and Kamal Menghrajani and Bolton, {Kelly L.} and Pierre Fenaux and Andrea Pellagatti and Uwe Platzbecker and Michael Heuser and Peter Valent and Shigeru Chiba and Yasushi Miyazaki and Carlo Finelli and Voso, {Maria Teresa} and Shih, {Lee Yung} and Michaela Fontenay and Jansen, {Joop H.} and Jos{\'e} Cervera and Yoshiko Atsuta and Norbert Gattermann and Ebert, {Benjamin L.} and Rafael Bejar and Greenberg, {Peter L.} and Mario Cazzola and Eva Hellstr{\"o}m-Lindberg and Seishi Ogawa and Elli Papaemmanuil",

year = "2020",

month = oct,

day = "1",

doi = "10.1038/s41591-020-1008-z",

language = "English",

volume = "26",

pages = "1549--1556",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "10",

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Bernard, E, Nannya, Y, Hasserjian, RP, Devlin, SM, Tuechler, H, Medina-Martinez, JS, Yoshizato, T, Shiozawa, Y, Saiki, R, Malcovati, L, Levine, MF, Arango, JE, Zhou, Y, Solé, F, Cargo, CA, Haase, D, Creignou, M, Germing, U, Zhang, Y, Gundem, G, Sarian, A, van de Loosdrecht, AA, Jädersten, M, Tobiasson, M, Kosmider, O, Follo, MY, Thol, F, Pinheiro, RF, Santini, V, Kotsianidis, I, Boultwood, J, Santos, FPS, Schanz, J, Kasahara, S, Ishikawa, T, Tsurumi, H, Takaori-Kondo, A, Kiguchi, T, Polprasert, C, Bennett, JM, Klimek, VM, Savona, MR, Belickova, M, Ganster, C, Palomo, L, Sanz, G, Ades, L, Della Porta, MG, Smith, AG, Werner, Y, Patel, M, Viale, A, Vanness, K, Neuberg, DS, Stevenson, KE, Menghrajani, K, Bolton, KL, Fenaux, P, Pellagatti, A, Platzbecker, U, Heuser, M, Valent, P, Chiba, S, Miyazaki, Y, Finelli, C, Voso, MT, Shih, LY, Fontenay, M, Jansen, JH, Cervera, J, Atsuta, Y, Gattermann, N, Ebert, BL, Bejar, R, Greenberg, PL, Cazzola, M, Hellström-Lindberg, E, Ogawa, S & Papaemmanuil, E 2020, 'Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes', Nature Medicine, vol. 26, no. 10, pp. 1549-1556. https://doi.org/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.

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.

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U2 - 10.1038/s41591-020-1008-z

DO - 10.1038/s41591-020-1008-z

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