-
Something wrong with this record ?
Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
E. Bernard, Y. Nannya, RP. Hasserjian, SM. Devlin, H. Tuechler, JS. Medina-Martinez, T. Yoshizato, Y. Shiozawa, R. Saiki, L. Malcovati, MF. Levine, JE. Arango, Y. Zhou, F. Solé, CA. Cargo, D. Haase, M. Creignou, U. Germing, Y. Zhang, G. Gundem,...
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Howard Hughes Medical Institute - United States
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Alleles MeSH
- Survival Analysis MeSH
- Phenotype MeSH
- Gene Frequency MeSH
- Cohort Studies MeSH
- Humans MeSH
- Mutation MeSH
- DNA Mutational Analysis MeSH
- Myelodysplastic Syndromes diagnosis genetics mortality therapy MeSH
- Tumor Suppressor Protein p53 genetics MeSH
- Genomic Instability genetics MeSH
- Prognosis MeSH
- DNA Copy Number Variations genetics MeSH
- Treatment Outcome MeSH
- Loss of Heterozygosity genetics MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Cancer Center Humanitas Research Hospital and Humanitas University Milan Italy
Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY USA
Chang Gung Memorial Hospital at Linkou Chang Gung University Taoyuan City Taiwan
Clinics of Hematology and Medical Oncology University Medical Center Göttingen Germany
Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy
Department of Data Sciences Dana Farber Cancer Institute Boston MA USA
Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA
Department of Genomics Institute of Hematology and Blood Transfusion Prague Czech Republic
Department of Health Sciences University of York York UK
Department of Hematology and Genetics Unit University Hospital La Fe Valencia Spain
Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan
Department of Hematology Atomic Bomb Disease Institute Nagasaki University Nagasaki Japan
Department of Hematology Chugoku Central Hospital Fukuyama Japan
Department of Hematology Democritus University of Thrace Medical School Alexandroupolis Greece
Department of Hematology Faculty of Medicine University of Tsukuba Tsukuba Japan
Department of Hematology Gifu Municipal Hospital Gifu Japan
Department of Hematology Gifu University Graduate School of Medicine Gifu Japan
Department of Hematology Hôpital St Louis and Paris University Paris France
Department of Hematology Kobe City Medical Center General Hospital Kobe Japan
Department of Hematology VU University Medical Center Amsterdam Amsterdam the Netherlands
Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA
Department of Pathology and Tumor Biology Kyoto University Kyoto Japan
Department of Pathology Massachusetts General Hospital Boston MA USA
Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA
Drug Research and Development Center Federal University of Ceara Ceara Brazil
Haematological Malignancy Diagnostic Service St James's University Hospital Leeds UK
Institute of Hematology S Orsola Malpighi University Hospital Bologna Italy
Integrated Genomics Operation Memorial Sloan Kettering Cancer Center New York NY USA
Japanese Data Center for Hematopoietic Cell Transplantation Nagoya Japan
Laboratory Hematology Department LABGK Radboud University Medical Centre Nijmegen the Netherlands
MDS Group Institut de Recerca Contra la Leucèmia Josep Carreras Barcelona Spain
MDS Unit Hematology AOU Careggi University of Florence Florence Italy
Oncology Hematology Center Hospital Israelita Albert Einstein São Paulo Brazil
Radcliffe Department of Medicine University of Oxford and Oxford BRC Haematology Theme Oxford UK
Stanford University Cancer Institute Stanford CA USA
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc20027791
- 003
- CZ-PrNML
- 005
- 20210114152357.0
- 007
- ta
- 008
- 210105s2020 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1038/s41591-020-1008-z $2 doi
- 035 __
- $a (PubMed)32747829
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Bernard, Elsa $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 245 10
- $a Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes / $c E. Bernard, Y. Nannya, RP. Hasserjian, SM. Devlin, H. Tuechler, JS. Medina-Martinez, T. Yoshizato, Y. Shiozawa, R. Saiki, L. Malcovati, MF. Levine, JE. Arango, Y. Zhou, F. Solé, CA. Cargo, D. Haase, M. Creignou, U. Germing, Y. Zhang, G. Gundem, A. Sarian, AA. van de Loosdrecht, M. Jädersten, M. Tobiasson, O. Kosmider, MY. Follo, F. Thol, RF. Pinheiro, V. Santini, I. Kotsianidis, J. Boultwood, FPS. Santos, J. Schanz, S. Kasahara, T. Ishikawa, H. Tsurumi, A. Takaori-Kondo, T. Kiguchi, C. Polprasert, JM. Bennett, VM. Klimek, MR. Savona, M. Belickova, C. Ganster, L. Palomo, G. Sanz, L. Ades, MG. Della Porta, AG. Smith, Y. Werner, M. Patel, A. Viale, K. Vanness, DS. Neuberg, KE. Stevenson, K. Menghrajani, KL. Bolton, P. Fenaux, A. Pellagatti, U. Platzbecker, M. Heuser, P. Valent, S. Chiba, Y. Miyazaki, C. Finelli, MT. Voso, LY. Shih, M. Fontenay, JH. Jansen, J. Cervera, Y. Atsuta, N. Gattermann, BL. Ebert, R. Bejar, PL. Greenberg, M. Cazzola, E. Hellström-Lindberg, S. Ogawa, E. Papaemmanuil,
- 520 9_
- $a 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.
- 650 _2
- $a alely $7 D000483
- 650 _2
- $a kohortové studie $7 D015331
- 650 _2
- $a variabilita počtu kopií segmentů DNA $x genetika $7 D056915
- 650 _2
- $a mutační analýza DNA $7 D004252
- 650 _2
- $a ženské pohlaví $7 D005260
- 650 _2
- $a frekvence genu $7 D005787
- 650 _2
- $a nestabilita genomu $x genetika $7 D042822
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a ztráta heterozygozity $x genetika $7 D019656
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 _2
- $a mutace $7 D009154
- 650 _2
- $a myelodysplastické syndromy $x diagnóza $x genetika $x mortalita $x terapie $7 D009190
- 650 _2
- $a fenotyp $7 D010641
- 650 _2
- $a prognóza $7 D011379
- 650 _2
- $a analýza přežití $7 D016019
- 650 _2
- $a výsledek terapie $7 D016896
- 650 _2
- $a nádorový supresorový protein p53 $x genetika $7 D016159
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Nannya, Yasuhito $u Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
- 700 1_
- $a Hasserjian, Robert P $u Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
- 700 1_
- $a Devlin, Sean M $u Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Tuechler, Heinz $u , Vienna, Austria.
- 700 1_
- $a Medina-Martinez, Juan S $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Yoshizato, Tetsuichi $u Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
- 700 1_
- $a Shiozawa, Yusuke $u Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
- 700 1_
- $a Saiki, Ryunosuke $u Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
- 700 1_
- $a Malcovati, Luca $u Department of Molecular Medicine, University of Pavia, Pavia, Italy. Department of Hematology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy.
- 700 1_
- $a Levine, Max F $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Arango, Juan E $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Zhou, Yangyu $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Solé, Francesc $u MDS Group, Institut de Recerca Contra la Leucèmia Josep Carreras, Barcelona, Spain.
- 700 1_
- $a Cargo, Catherine A $u Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, UK.
- 700 1_
- $a Haase, Detlef $u Clinics of Hematology and Medical Oncology, University Medical Center, Göttingen, Germany.
- 700 1_
- $a Creignou, Maria $u Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- 700 1_
- $a Germing, Ulrich $u Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
- 700 1_
- $a Zhang, Yanming $u Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Gundem, Gunes $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Sarian, Araxe $u Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a van de Loosdrecht, Arjan A $u Department of Hematology, VU University Medical Center Amsterdam, Amsterdam, the Netherlands.
- 700 1_
- $a Jädersten, Martin $u Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- 700 1_
- $a Tobiasson, Magnus $u Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- 700 1_
- $a Kosmider, Olivier $u Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin and Université de Paris, Université Paris Descartes, Paris, France.
- 700 1_
- $a Follo, Matilde Y $u Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
- 700 1_
- $a Thol, Felicitas $u Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation Hannover Medical School, Hannover, Germany.
- 700 1_
- $a Pinheiro, Ronald F $u Drug Research and Development Center, Federal University of Ceara, Ceara, Brazil.
- 700 1_
- $a Santini, Valeria $u MDS Unit, Hematology, AOU Careggi, University of Florence, Florence, Italy.
- 700 1_
- $a Kotsianidis, Ioannis $u Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.
- 700 1_
- $a Boultwood, Jacqueline $u Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, UK.
- 700 1_
- $a Santos, Fabio P S $u Oncology-Hematology Center, Hospital Israelita Albert Einstein, São Paulo, Brazil.
- 700 1_
- $a Schanz, Julie $u Clinics of Hematology and Medical Oncology, University Medical Center, Göttingen, Germany.
- 700 1_
- $a Kasahara, Senji $u Department of Hematology, Gifu Municipal Hospital, Gifu, Japan.
- 700 1_
- $a Ishikawa, Takayuki $u Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
- 700 1_
- $a Tsurumi, Hisashi $u Department of Hematology, Gifu University Graduate School of Medicine, Gifu, Japan.
- 700 1_
- $a Takaori-Kondo, Akifumi $u Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- 700 1_
- $a Kiguchi, Toru $u Department of Hematology, Chugoku Central Hospital, Fukuyama, Japan.
- 700 1_
- $a Polprasert, Chantana $u Department of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
- 700 1_
- $a Bennett, John M $u Lab. Medicine and Pathology, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.
- 700 1_
- $a Klimek, Virginia M $u Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Savona, Michael R $u Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- 700 1_
- $a Belickova, Monika $u Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
- 700 1_
- $a Ganster, Christina $u Clinics of Hematology and Medical Oncology, University Medical Center, Göttingen, Germany.
- 700 1_
- $a Palomo, Laura $u MDS Group, Institut de Recerca Contra la Leucèmia Josep Carreras, Barcelona, Spain.
- 700 1_
- $a Sanz, Guillermo $u Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain. CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
- 700 1_
- $a Ades, Lionel $u Department of Hematology, Hôpital St Louis and Paris University, Paris, France.
- 700 1_
- $a Della Porta, Matteo Giovanni $u Cancer Center, Humanitas Research Hospital & Humanitas University, Milan, Italy.
- 700 1_
- $a Smith, Alexandra G $u Department of Health Sciences, University of York, York, UK.
- 700 1_
- $a Werner, Yesenia $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Patel, Minal $u Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Viale, Agnès $u Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Vanness, Katelynd $u Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Neuberg, Donna S $u Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
- 700 1_
- $a Stevenson, Kristen E $u Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
- 700 1_
- $a Menghrajani, Kamal $u Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Bolton, Kelly L $u Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 700 1_
- $a Fenaux, Pierre $u Department of Hematology, Hôpital St Louis and Paris University, Paris, France.
- 700 1_
- $a Pellagatti, Andrea $u Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, UK.
- 700 1_
- $a Platzbecker, Uwe $u Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University of Leipzig, Leipzig, Germany.
- 700 1_
- $a Heuser, Michael $u Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation Hannover Medical School, Hannover, Germany.
- 700 1_
- $a Valent, Peter $u Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
- 700 1_
- $a Chiba, Shigeru $u Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
- 700 1_
- $a Miyazaki, Yasushi $u Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
- 700 1_
- $a Finelli, Carlo $u Institute of Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
- 700 1_
- $a Voso, Maria Teresa $u MDS Cooperative Group GROM-L, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
- 700 1_
- $a Shih, Lee-Yung $u Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan City, Taiwan.
- 700 1_
- $a Fontenay, Michaela $u Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin and Université de Paris, Université Paris Descartes, Paris, France.
- 700 1_
- $a Jansen, Joop H $u Laboratory Hematology, Department LABGK, Radboud University Medical Centre, Nijmegen, the Netherlands.
- 700 1_
- $a Cervera, José $u Department of Hematology and Genetics Unit, University Hospital La Fe, Valencia, Spain.
- 700 1_
- $a Atsuta, Yoshiko $u Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.
- 700 1_
- $a Gattermann, Norbert $u Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.
- 700 1_
- $a Ebert, Benjamin L $u Department of Medical Oncology and Howard Hughes Medical Institute, Dana-Farber Cancer Center, Boston, MA, USA.
- 700 1_
- $a Bejar, Rafael $u UC San Diego Moores Cancer Center, La Jolla, CA, USA.
- 700 1_
- $a Greenberg, Peter L $u Stanford University Cancer Institute, Stanford, CA, USA.
- 700 1_
- $a Cazzola, Mario $u Department of Molecular Medicine, University of Pavia, Pavia, Italy. Department of Hematology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy.
- 700 1_
- $a Hellström-Lindberg, Eva $u Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- 700 1_
- $a Ogawa, Seishi $u Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
- 700 1_
- $a Papaemmanuil, Elli $u Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. papaemme@mskcc.org. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. papaemme@mskcc.org.
- 773 0_
- $w MED00003459 $t Nature medicine $x 1546-170X $g Roč. 26, č. 10 (2020), s. 1549-1556
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/32747829 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20210105 $b ABA008
- 991 __
- $a 20210114152354 $b ABA008
- 999 __
- $a ok $b bmc $g 1608126 $s 1118971
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2020 $b 26 $c 10 $d 1549-1556 $e 20200803 $i 1546-170X $m Nature medicine $n Nat Med $x MED00003459
- GRA __
- $p Howard Hughes Medical Institute $2 United States
- LZP __
- $a Pubmed-20210105
