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

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

200 Scopus citations

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
State	Published - Oct 1 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

@article{aca43358d30647f7a4ae4cacd1c941a3,

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",

note = "Funding Information: The authors declare the following competing interests. U.G. has received honoraria from Celgene, Novartis, Amgen, Janssen, Roche and Jazz and research funding from Celgene and Novartis. C.A.C. has received research funding from Celgene. A.A.L. is in advisory boards of Celgene, Amgen, Roche, Novartis and Alexion and has received research funding from Celgene. F.T. is on the advisory boards of Jazz, Pfizzer and Abbvie and has received research funding from Celgene. I.K. is on the advisory board of Genesis Pharma and has received research funding from Celgene and Janssen Hellas. F.P.S.S. has received honoraria from Janssen-Cilag, Bristol-Myers-Squibb, Novartis, Amgen, Abbvie and Pfizer, is on the advisory boards of Novartis, Amgen and Abbvie and has received research funding from Novartis. A.T.-K. has received honoraria from Novartis, Bristol-Myers-Squibb and MSD and has received research funding from Celgene, Ono Pharmaceutical and Cognano. T.K. has received research funding from Bristol-Myers-Squibb, Otsuka Pharmaceutical, Kyowa Kirin, MSD, Astellas Pharmaceutical, Nippon Shinyaku, Novartis Pharmaceutical, Sumitomo Dainippon Pharmaceutical, Janssen Pharmaceutical, Celgene, SymBio Pharmaceutical, Taiho Pharmaceutical, Tejin, Sanofi K.K. and Celltrion. M.R.S. is on the advisory boards of Abbvie, Astex, Celgene, Karyopharm, Selvita and TG Therapeutic, has equity in Karyopharm and has received research funding from Astex, Incyte, Sunesis, Takeda and TG Therapeutics. G.S. is on the advisory boards of AbbVie, Amgen, Astellas, B{\"o}ehringer-Ingelheim, Celgene, Helsinn Healthcare, Hoffmann-La Roche, Janssen-Cilag, Novartis and Onconova and has received research funding from Celgene, Hoffmann-La Roche, Janssen-Cilag and Novartis. L.A. is on the advisory boards of Abbvie, Astex, Celgene and Novartis and has received research funding from Celgene. D.S.N. has equity in Madrigal Phamaceuticals and has received research funding from Celgene and Pharmacyclics. K.L.B. has received research funding from GRAIL. M.H. has received honoraria from Novartis, Pfizer and PriME Oncology, is on the advisory boards of Abbvie, Bayer Pharma, Daiichi Sankyo, Novartis and Pfizer and has received institutional research funding from Astellas, Bayer Pharma, BergenBio, Daiichi Sankyo, Karyopharm, Novartis, Pfizer and Roche. P.V. has received honoraria and research funding from Celgene. S.C. has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Takeda Pharmaceutical, Astellas Pharmaceutical, Sanofi KK and Ono Pharmaceutical. Y.M. has received honoraria from Ohtsuka, Novartis, Nippon Shinyaku, Dainippon-Sumitomo and Kyowa Kirin and research funding from Chugai. C.F. is on the advisory boards of, and has received honoraria from, Celgene, Novartis and Janssen and has received research funding from Celgene. M.T.V. is on the advisory board of Celgene, has received honoraria from Celgene and Novartis and has received research funding from Celgene. Y.A. has received honoraria from Mochida, Meiji, Chugai and Kyowa Kirin. N.G. is on the advisory board of, and has received honoraria from, Novartis and has received research funding from Alexion. B.L.E. has received research funding from Celgene and Deerfield. R.B. is on the advisory boards of Celgene, AbbVie, Astex, NeoGenomics and Daiichi Sankyo and has received research funding from Celgene and Takeda. E.H.-L. has received research funding from Celgene. E.B. has received research funding from Celgene. E.P. has received research funding from Celgene and has served on scientific advisory boards for Novartis. E.P. is the founder and CEO of Isabl, a company offering analytics for cancer whole-genome sequencing data. Funding Information: This work was supported in part by grants from the Celgene Corporation through the MDS Foundation. It was also supported by grants-in-aid from the Japan Agency for Medical Research and Development (AMED) (JP19cm0106501, JP19ck0106250 and 15H05909 (S.O.) and JP18ck0106353 (Y.N.)), from the Japan Society for the Promotion of Science (JSPS) (KAKEN JP26221308, JP19H05656 (S.O.)) and from the Ministry of Education, Culture, Sports, Science and Technology (hp160219 (S.O.)). J.B. and A.P. acknowledge funding from Blood Cancer UK (grant 13042). P.V. was supported by the Austrian Science Fund (grant F4704-B20). M.Y.F. was supported by Italian MIUR-PRIN grants. L.M. was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy) 5per Mille project (21267 and IG 20125). M.T.V. was supported by AIRC5 per Mille project (21267). M.T.V. recruited patients through the GROM-L clinical network. E.B. was supported by the Francois Wallace Monahan Fellowship and an EvansMDS Young Investigator award. E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, the American Society of Hematology, Gabrielle{\textquoteright}s Angels Foundation, V Foundation and The Geoffrey Beene Foundation. We thank T. Iraca for logistical support. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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",

number = "10",

}

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

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

N1 - Funding Information: The authors declare the following competing interests. U.G. has received honoraria from Celgene, Novartis, Amgen, Janssen, Roche and Jazz and research funding from Celgene and Novartis. C.A.C. has received research funding from Celgene. A.A.L. is in advisory boards of Celgene, Amgen, Roche, Novartis and Alexion and has received research funding from Celgene. F.T. is on the advisory boards of Jazz, Pfizzer and Abbvie and has received research funding from Celgene. I.K. is on the advisory board of Genesis Pharma and has received research funding from Celgene and Janssen Hellas. F.P.S.S. has received honoraria from Janssen-Cilag, Bristol-Myers-Squibb, Novartis, Amgen, Abbvie and Pfizer, is on the advisory boards of Novartis, Amgen and Abbvie and has received research funding from Novartis. A.T.-K. has received honoraria from Novartis, Bristol-Myers-Squibb and MSD and has received research funding from Celgene, Ono Pharmaceutical and Cognano. T.K. has received research funding from Bristol-Myers-Squibb, Otsuka Pharmaceutical, Kyowa Kirin, MSD, Astellas Pharmaceutical, Nippon Shinyaku, Novartis Pharmaceutical, Sumitomo Dainippon Pharmaceutical, Janssen Pharmaceutical, Celgene, SymBio Pharmaceutical, Taiho Pharmaceutical, Tejin, Sanofi K.K. and Celltrion. M.R.S. is on the advisory boards of Abbvie, Astex, Celgene, Karyopharm, Selvita and TG Therapeutic, has equity in Karyopharm and has received research funding from Astex, Incyte, Sunesis, Takeda and TG Therapeutics. G.S. is on the advisory boards of AbbVie, Amgen, Astellas, Böehringer-Ingelheim, Celgene, Helsinn Healthcare, Hoffmann-La Roche, Janssen-Cilag, Novartis and Onconova and has received research funding from Celgene, Hoffmann-La Roche, Janssen-Cilag and Novartis. L.A. is on the advisory boards of Abbvie, Astex, Celgene and Novartis and has received research funding from Celgene. D.S.N. has equity in Madrigal Phamaceuticals and has received research funding from Celgene and Pharmacyclics. K.L.B. has received research funding from GRAIL. M.H. has received honoraria from Novartis, Pfizer and PriME Oncology, is on the advisory boards of Abbvie, Bayer Pharma, Daiichi Sankyo, Novartis and Pfizer and has received institutional research funding from Astellas, Bayer Pharma, BergenBio, Daiichi Sankyo, Karyopharm, Novartis, Pfizer and Roche. P.V. has received honoraria and research funding from Celgene. S.C. has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Takeda Pharmaceutical, Astellas Pharmaceutical, Sanofi KK and Ono Pharmaceutical. Y.M. has received honoraria from Ohtsuka, Novartis, Nippon Shinyaku, Dainippon-Sumitomo and Kyowa Kirin and research funding from Chugai. C.F. is on the advisory boards of, and has received honoraria from, Celgene, Novartis and Janssen and has received research funding from Celgene. M.T.V. is on the advisory board of Celgene, has received honoraria from Celgene and Novartis and has received research funding from Celgene. Y.A. has received honoraria from Mochida, Meiji, Chugai and Kyowa Kirin. N.G. is on the advisory board of, and has received honoraria from, Novartis and has received research funding from Alexion. B.L.E. has received research funding from Celgene and Deerfield. R.B. is on the advisory boards of Celgene, AbbVie, Astex, NeoGenomics and Daiichi Sankyo and has received research funding from Celgene and Takeda. E.H.-L. has received research funding from Celgene. E.B. has received research funding from Celgene. E.P. has received research funding from Celgene and has served on scientific advisory boards for Novartis. E.P. is the founder and CEO of Isabl, a company offering analytics for cancer whole-genome sequencing data. Funding Information: This work was supported in part by grants from the Celgene Corporation through the MDS Foundation. It was also supported by grants-in-aid from the Japan Agency for Medical Research and Development (AMED) (JP19cm0106501, JP19ck0106250 and 15H05909 (S.O.) and JP18ck0106353 (Y.N.)), from the Japan Society for the Promotion of Science (JSPS) (KAKEN JP26221308, JP19H05656 (S.O.)) and from the Ministry of Education, Culture, Sports, Science and Technology (hp160219 (S.O.)). J.B. and A.P. acknowledge funding from Blood Cancer UK (grant 13042). P.V. was supported by the Austrian Science Fund (grant F4704-B20). M.Y.F. was supported by Italian MIUR-PRIN grants. L.M. was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy) 5per Mille project (21267 and IG 20125). M.T.V. was supported by AIRC5 per Mille project (21267). M.T.V. recruited patients through the GROM-L clinical network. E.B. was supported by the Francois Wallace Monahan Fellowship and an EvansMDS Young Investigator award. E.P. is a Josie Robertson Investigator and is supported by the European Hematology Association, the American Society of Hematology, Gabrielle’s Angels Foundation, V Foundation and The Geoffrey Beene Foundation. We thank T. Iraca for logistical support. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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

M3 - Article

C2 - 32747829

AN - SCOPUS:85088857953

SN - 1078-8956

VL - 26

SP - 1549

EP - 1556

JO - Nature Medicine

JF - Nature Medicine

IS - 10

ER -

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

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