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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-08-03

AUTHORS

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, Harold K. Elias, 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

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. More... »

PAGES

1549-1556

Journal

TITLE

Nature Medicine

ISSUE

10

VOLUME

26

Author Affiliations

  • Center for Hematologic Malignancies, 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 Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Vienna, Austria
  • Department of Hematology, IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy
  • MDS Group, Institut de Recerca Contra la Leucèmia Josep Carreras, Barcelona, Spain
  • Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds, UK
  • Clinics of Hematology and Medical Oncology, University Medical Center, Göttingen, Germany
  • Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  • Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany
  • Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Department of Hematology, VU University Medical Center Amsterdam, Amsterdam, the Netherlands
  • Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin and Université de Paris, Université Paris Descartes, Paris, France
  • Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
  • Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation Hannover Medical School, Hannover, Germany
  • Drug Research and Development Center, Federal University of Ceara, Ceara, Brazil
  • MDS Unit, Hematology, AOU Careggi, University of Florence, Florence, Italy
  • Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
  • Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, UK
  • Oncology-Hematology Center, Hospital Israelita Albert Einstein, São Paulo, Brazil
  • Department of Hematology, Gifu Municipal Hospital, Gifu, Japan
  • Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan
  • Department of Hematology, Gifu University Graduate School of Medicine, Gifu, Japan
  • Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • Department of Hematology, Chugoku Central Hospital, Fukuyama, Japan
  • Department of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
  • Lab. Medicine and Pathology, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  • Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
  • CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
  • Department of Hematology, Hôpital St Louis and Paris University, Paris, France
  • Department of Biomedical Sciences, Humanitas University, Milan, Italy
  • Department of Health Sciences, University of York, York, UK
  • Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
  • Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University of Leipzig, Leipzig, Germany
  • Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
  • Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  • Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
  • Institute of Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy
  • MDS Cooperative Group GROM-L, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy
  • Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan City, Taiwan
  • Laboratory Hematology, Department LABGK, Radboud University Medical Centre, Nijmegen, the Netherlands
  • Department of Hematology and Genetics Unit, University Hospital La Fe, Valencia, Spain
  • Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
  • Department of Medical Oncology and Howard Hughes Medical Institute, Dana-Farber Cancer Center, Boston, MA, USA
  • UC San Diego Moores Cancer Center, La Jolla, CA, USA
  • Stanford University Cancer Institute, Stanford, CA, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41591-020-1008-z

    DOI

    http://dx.doi.org/10.1038/s41591-020-1008-z

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1129832859

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32747829


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