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.

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

CIBERONC Instituto de Salud Carlos 3 Madrid Spain

Clinics of Hematology and Medical Oncology University Medical Center Göttingen Germany

Computational Oncology Service Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Biomedical Sciences Humanitas University Milan 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 Assistance Publique Hôpitaux de Paris Hôpital Cochin and Université de Paris Université Paris Descartes Paris France

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 Hemostasis Oncology and Stem Cell Transplantation Hannover Medical School Hannover Germany

Department of Hematology Hôpital St Louis and Paris University Paris France

Department of Hematology Hospital Universitario y Politécnico La Fe Valencia Spain

Department of Hematology IRCCS Fondazione Policlinico S Matteo Pavia Italy

Department of Hematology Kobe City Medical Center General Hospital Kobe Japan

Department of Hematology Oncology and Clinical Immunology Heinrich Heine University Düsseldorf Germany

Department of Hematology VU University Medical Center Amsterdam Amsterdam the Netherlands

Department of Internal Medicine 1 Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna Austria

Department of Medical Oncology and Howard Hughes Medical Institute Dana Farber Cancer Center Boston MA USA

Department of Medicine Chulalongkorn University King Chulalongkorn Memorial Hospital Bangkok Thailand

Department of Medicine Huddinge Center for Hematology and Regenerative Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

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 Molecular Medicine University of Pavia Pavia Italy

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

Humanitas Clinical and Research Center IRCCS Humanitas Cancer Center Milan Italy

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

Lab Medicine and Pathology Hematology Oncology University of Rochester Medical Center Rochester NY USA

Laboratory Hematology Department LABGK Radboud University Medical Centre Nijmegen the Netherlands

MDS Cooperative Group GROM L Department of Biomedicine and Prevention Tor Vergata University Rome Italy

MDS Group Institut de Recerca Contra la Leucèmia Josep Carreras Barcelona Spain

MDS Unit Hematology AOU Careggi University of Florence Florence Italy

Medical Clinic and Policlinic 1 Hematology and Cellular Therapy University of Leipzig Leipzig Germany

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

UC San Diego Moores Cancer Center La Jolla CA USA

Vienna Austria

Comment In

Cancer Discov. 2020 Nov;10(11):1616. doi: 10.1158/2159-8290.CD-NB2020-088. PubMed

Erratum In

Nat Med. 2021 Mar;27(3):562. doi: 10.1038/s41591-021-01253-5. PubMed

Erratum In

Nat Med. 2021 May;27(5):927. doi: 10.1038/s41591-021-01367-w. PubMed

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