TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups

International Working Group for MDS Molecular Prognostic Committee, Detlef Haase, Kristen E. Stevenson, Donna Neuberg, Jaroslaw P. Maciejewski, Aziz Nazha, Mikkael A. Sekeres, Benjamin L. Ebert, Guillermo Garcia-Manero, Claudia Haferlach, Torsten Haferlach, Wolfgang Kern, Seishi Ogawa, Yasunobu Nagata, Kenichi Yoshida, Timothy A. Graubert, Matthew J. Walter, Alan F. List, Rami S. Komrokji, Eric PadronDavid Sallman, Elli Papaemmanuil, Peter J. Campbell, Michael R. Savona, Adam Seegmiller, Lionel Adès, Pierre Fenaux, Lee Yung Shih, David Bowen, Michael J. Groves, Sudhir Tauro, Michaela Fontenay, Olivier Kosmider, Michal Bar-Natan, David Steensma, Richard Stone, Michael Heuser, Felicitas Thol, Mario Cazzola, Luca Malcovati, Aly Karsan, Christina Ganster, Eva Hellström-Lindberg, Jacqueline Boultwood, Andrea Pellagatti, Valeria Santini, Lynn Quek, Paresh Vyas, Heinz Tüchler, Peter L. Greenberg, Rafael Bejar

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Abstract

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p < 0.005), monosomal karyotype (p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

Original languageEnglish
Pages (from-to)1747-1758
Number of pages12
JournalLeukemia
Volume33
Issue number7
Early online date11 Jan 2019
DOIs
Publication statusPublished - Jul 2019

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Myelodysplastic Syndromes
Karyotype
Mutation
Chromosome Aberrations
Critical Care
Survival
Genes

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International Working Group for MDS Molecular Prognostic Committee, Haase, D., Stevenson, K. E., Neuberg, D., Maciejewski, J. P., Nazha, A., ... Bejar, R. (2019). TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia, 33(7), 1747-1758. https://doi.org/10.1038/s41375-018-0351-2
International Working Group for MDS Molecular Prognostic Committee ; Haase, Detlef ; Stevenson, Kristen E. ; Neuberg, Donna ; Maciejewski, Jaroslaw P. ; Nazha, Aziz ; Sekeres, Mikkael A. ; Ebert, Benjamin L. ; Garcia-Manero, Guillermo ; Haferlach, Claudia ; Haferlach, Torsten ; Kern, Wolfgang ; Ogawa, Seishi ; Nagata, Yasunobu ; Yoshida, Kenichi ; Graubert, Timothy A. ; Walter, Matthew J. ; List, Alan F. ; Komrokji, Rami S. ; Padron, Eric ; Sallman, David ; Papaemmanuil, Elli ; Campbell, Peter J. ; Savona, Michael R. ; Seegmiller, Adam ; Adès, Lionel ; Fenaux, Pierre ; Shih, Lee Yung ; Bowen, David ; Groves, Michael J. ; Tauro, Sudhir ; Fontenay, Michaela ; Kosmider, Olivier ; Bar-Natan, Michal ; Steensma, David ; Stone, Richard ; Heuser, Michael ; Thol, Felicitas ; Cazzola, Mario ; Malcovati, Luca ; Karsan, Aly ; Ganster, Christina ; Hellström-Lindberg, Eva ; Boultwood, Jacqueline ; Pellagatti, Andrea ; Santini, Valeria ; Quek, Lynn ; Vyas, Paresh ; Tüchler, Heinz ; Greenberg, Peter L. ; Bejar, Rafael. / TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. In: Leukemia. 2019 ; Vol. 33, No. 7. pp. 1747-1758.
@article{848c99564339408eb3618f93282fad10,
title = "TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups",
abstract = "Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10{\%} have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55{\%} of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p < 0.005), monosomal karyotype (p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10{\%}), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.",
author = "{International Working Group for MDS Molecular Prognostic Committee} and Detlef Haase and Stevenson, {Kristen E.} and Donna Neuberg and Maciejewski, {Jaroslaw P.} and Aziz Nazha and Sekeres, {Mikkael A.} and Ebert, {Benjamin L.} and Guillermo Garcia-Manero and Claudia Haferlach and Torsten Haferlach and Wolfgang Kern and Seishi Ogawa and Yasunobu Nagata and Kenichi Yoshida and Graubert, {Timothy A.} and Walter, {Matthew J.} and List, {Alan F.} and Komrokji, {Rami S.} and Eric Padron and David Sallman and Elli Papaemmanuil and Campbell, {Peter J.} and Savona, {Michael R.} and Adam Seegmiller and Lionel Ad{\`e}s and Pierre Fenaux and Shih, {Lee Yung} and David Bowen and Groves, {Michael J.} and Sudhir Tauro and Michaela Fontenay and Olivier Kosmider and Michal Bar-Natan and David Steensma and Richard Stone and Michael Heuser and Felicitas Thol and Mario Cazzola and Luca Malcovati and Aly Karsan and Christina Ganster and Eva Hellstr{\"o}m-Lindberg and Jacqueline Boultwood and Andrea Pellagatti and Valeria Santini and Lynn Quek and Paresh Vyas and Heinz T{\"u}chler and Greenberg, {Peter L.} and Rafael Bejar",
note = "We would like to thank the MDS Foundation for their support of the International Working Group for MDS and Celgene for funding the efforts of the IWG-prognosis molecular subcommittee and this study. RB was additionally supported by K08 DK091360. PV acknowledges funding from the MRC Disease Team Awards (G1000729/94931 and MR/L008963/1) MRC Molecular Haematology Unit and the Oxford Partnership Comprehensive Biomedical Research Centre (NIHR BRC Funding scheme. oxfbrc-2012–1). LQ is funded by an MRC Clinician Scientist Fellowship. JB and AP acknowledge funding from Bloodwise (UK). LM acknowledges funding from Associazione Italiana per la Ricerca sul Cancro (AIRC, Individual Grant 20125). MH acknowledges funding from DFG grant HE 5240/6–1.",
year = "2019",
month = "7",
doi = "10.1038/s41375-018-0351-2",
language = "English",
volume = "33",
pages = "1747--1758",
journal = "Leukemia",
issn = "0887-6924",
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International Working Group for MDS Molecular Prognostic Committee, Haase, D, Stevenson, KE, Neuberg, D, Maciejewski, JP, Nazha, A, Sekeres, MA, Ebert, BL, Garcia-Manero, G, Haferlach, C, Haferlach, T, Kern, W, Ogawa, S, Nagata, Y, Yoshida, K, Graubert, TA, Walter, MJ, List, AF, Komrokji, RS, Padron, E, Sallman, D, Papaemmanuil, E, Campbell, PJ, Savona, MR, Seegmiller, A, Adès, L, Fenaux, P, Shih, LY, Bowen, D, Groves, MJ, Tauro, S, Fontenay, M, Kosmider, O, Bar-Natan, M, Steensma, D, Stone, R, Heuser, M, Thol, F, Cazzola, M, Malcovati, L, Karsan, A, Ganster, C, Hellström-Lindberg, E, Boultwood, J, Pellagatti, A, Santini, V, Quek, L, Vyas, P, Tüchler, H, Greenberg, PL & Bejar, R 2019, 'TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups', Leukemia, vol. 33, no. 7, pp. 1747-1758. https://doi.org/10.1038/s41375-018-0351-2

TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. / International Working Group for MDS Molecular Prognostic Committee; Haase, Detlef; Stevenson, Kristen E.; Neuberg, Donna; Maciejewski, Jaroslaw P.; Nazha, Aziz; Sekeres, Mikkael A.; Ebert, Benjamin L.; Garcia-Manero, Guillermo; Haferlach, Claudia; Haferlach, Torsten; Kern, Wolfgang; Ogawa, Seishi; Nagata, Yasunobu; Yoshida, Kenichi; Graubert, Timothy A.; Walter, Matthew J.; List, Alan F.; Komrokji, Rami S.; Padron, Eric; Sallman, David; Papaemmanuil, Elli; Campbell, Peter J.; Savona, Michael R.; Seegmiller, Adam; Adès, Lionel; Fenaux, Pierre; Shih, Lee Yung; Bowen, David; Groves, Michael J.; Tauro, Sudhir; Fontenay, Michaela; Kosmider, Olivier; Bar-Natan, Michal; Steensma, David; Stone, Richard; Heuser, Michael; Thol, Felicitas; Cazzola, Mario; Malcovati, Luca; Karsan, Aly; Ganster, Christina; Hellström-Lindberg, Eva; Boultwood, Jacqueline; Pellagatti, Andrea; Santini, Valeria; Quek, Lynn; Vyas, Paresh; Tüchler, Heinz; Greenberg, Peter L.; Bejar, Rafael (Lead / Corresponding author).

In: Leukemia, Vol. 33, No. 7, 07.2019, p. 1747-1758.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups

AU - International Working Group for MDS Molecular Prognostic Committee

AU - Haase, Detlef

AU - Stevenson, Kristen E.

AU - Neuberg, Donna

AU - Maciejewski, Jaroslaw P.

AU - Nazha, Aziz

AU - Sekeres, Mikkael A.

AU - Ebert, Benjamin L.

AU - Garcia-Manero, Guillermo

AU - Haferlach, Claudia

AU - Haferlach, Torsten

AU - Kern, Wolfgang

AU - Ogawa, Seishi

AU - Nagata, Yasunobu

AU - Yoshida, Kenichi

AU - Graubert, Timothy A.

AU - Walter, Matthew J.

AU - List, Alan F.

AU - Komrokji, Rami S.

AU - Padron, Eric

AU - Sallman, David

AU - Papaemmanuil, Elli

AU - Campbell, Peter J.

AU - Savona, Michael R.

AU - Seegmiller, Adam

AU - Adès, Lionel

AU - Fenaux, Pierre

AU - Shih, Lee Yung

AU - Bowen, David

AU - Groves, Michael J.

AU - Tauro, Sudhir

AU - Fontenay, Michaela

AU - Kosmider, Olivier

AU - Bar-Natan, Michal

AU - Steensma, David

AU - Stone, Richard

AU - Heuser, Michael

AU - Thol, Felicitas

AU - Cazzola, Mario

AU - Malcovati, Luca

AU - Karsan, Aly

AU - Ganster, Christina

AU - Hellström-Lindberg, Eva

AU - Boultwood, Jacqueline

AU - Pellagatti, Andrea

AU - Santini, Valeria

AU - Quek, Lynn

AU - Vyas, Paresh

AU - Tüchler, Heinz

AU - Greenberg, Peter L.

AU - Bejar, Rafael

N1 - We would like to thank the MDS Foundation for their support of the International Working Group for MDS and Celgene for funding the efforts of the IWG-prognosis molecular subcommittee and this study. RB was additionally supported by K08 DK091360. PV acknowledges funding from the MRC Disease Team Awards (G1000729/94931 and MR/L008963/1) MRC Molecular Haematology Unit and the Oxford Partnership Comprehensive Biomedical Research Centre (NIHR BRC Funding scheme. oxfbrc-2012–1). LQ is funded by an MRC Clinician Scientist Fellowship. JB and AP acknowledge funding from Bloodwise (UK). LM acknowledges funding from Associazione Italiana per la Ricerca sul Cancro (AIRC, Individual Grant 20125). MH acknowledges funding from DFG grant HE 5240/6–1.

PY - 2019/7

Y1 - 2019/7

N2 - Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p < 0.005), monosomal karyotype (p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

AB - Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p < 0.005), monosomal karyotype (p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

UR - http://www.scopus.com/inward/record.url?scp=85059915986&partnerID=8YFLogxK

U2 - 10.1038/s41375-018-0351-2

DO - 10.1038/s41375-018-0351-2

M3 - Article

C2 - 30635634

AN - SCOPUS:85059915986

VL - 33

SP - 1747

EP - 1758

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 7

ER -

International Working Group for MDS Molecular Prognostic Committee, Haase D, Stevenson KE, Neuberg D, Maciejewski JP, Nazha A et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019 Jul;33(7):1747-1758. https://doi.org/10.1038/s41375-018-0351-2