1. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
- Author
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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, 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., Sole F., Cargo C.A., Haase D., Creignou M., Germing U., Zhang Y., Gundem G., Sarian A., van de Loosdrecht A.A., Jadersten M., Tobiasson M., Kosmider O., Follo M.Y., Thol F., Pinheiro R.F., Santini V., Kotsianidis I., Boultwood J., Santos F.P.S., Schanz J., Kasahara S., Ishikawa T., Tsurumi H., Takaori-Kondo A., Kiguchi T., Polprasert C., Bennett J.M., Klimek V.M., Savona M.R., Belickova M., Ganster C., Palomo L., Sanz G., Ades L., Della Porta M.G., Smith A.G., Werner Y., Patel M., Viale A., Vanness K., Neuberg D.S., Stevenson K.E., Menghrajani K., Bolton K.L., Fenaux P., Pellagatti A., Platzbecker U., Heuser M., Valent P., Chiba S., Miyazaki Y., Finelli C., Voso M.T., Shih L.-Y., Fontenay M., Jansen J.H., Cervera J., Atsuta Y., Gattermann N., Ebert B.L., Bejar R., Greenberg P.L., Cazzola M., Hellstrom-Lindberg E., Ogawa S., Papaemmanuil E., Hematology, and CCA - Cancer biology and immunology
- Subjects
Male ,0301 basic medicine ,Oncology ,endocrine system diseases ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,DNA Mutational Analysis ,Loss of Heterozygosity ,Medical and Health Sciences ,Cohort Studies ,Loss of heterozygosity ,0302 clinical medicine ,Gene Frequency ,2.1 Biological and endogenous factors ,Medicine ,Aetiology ,Cancer ,DNA Copy Number Variation ,Allele ,0303 health sciences ,Myeloid leukemia ,Hematology ,General Medicine ,Prognosis ,3. Good health ,Phenotype ,Treatment Outcome ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Cohort ,Female ,Survival Analysi ,Human ,medicine.medical_specialty ,DNA Copy Number Variations ,Prognosi ,Immunology ,Myelodysplastic Syndrome ,Locus (genetics) ,Article ,Genomic Instability ,General Biochemistry, Genetics and Molecular Biology ,DNA Mutational Analysi ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,Complex Karyotype ,Genetics ,Humans ,Clinical significance ,Allele frequency ,neoplasms ,Gene ,Alleles ,Survival analysis ,030304 developmental biology ,business.industry ,Myelodysplastic syndromes ,Stem Cell Research ,Settore MED/15 ,medicine.disease ,Survival Analysis ,030104 developmental biology ,Myelodysplastic Syndromes ,Mutation ,Cohort Studie ,Tumor Suppressor Protein p53 ,TP53 mutations, myelodyspastic syndromes, prognosis, lenalidomide ,business - 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. Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states of TP53 and clinical presentation
- Published
- 2020
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