Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation
Autor: | Donna Neuberg, Benjamin L. Ebert, R. Coleman Lindsley, Stephen R. Spellman, Peter V. Grauman, Katharine C. Hsu, Wael Saber, Corey Cutler, Michael D. Haagenson, Michael R. Verneris, Brenton G. Mar, Katharina Fleischhauer, Robert A. Redd, Joseph H. Antin, Zhen-Huan Hu, Stephanie J. Lee, Tao Wang |
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Rok vydání: | 2017 |
Předmět: |
Adult
Oncology medicine.medical_specialty Transplantation Conditioning Adolescent medicine.medical_treatment DNA Mutational Analysis Medizin Hematopoietic stem cell transplantation medicine.disease_cause Article Young Adult 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Humans Transplantation Homologous Young adult Child Survival analysis Mutation business.industry Hematopoietic Stem Cell Transplantation Proteins General Medicine Janus Kinase 2 Middle Aged Genes p53 Prognosis Survival Analysis Protein Phosphatase 2C Transplantation Haematopoiesis Myelodysplastic Syndromes 030220 oncology & carcinogenesis Immunology ras Proteins Stem cell business 030215 immunology |
Zdroj: | New England Journal of Medicine. 376:536-547 |
ISSN: | 1533-4406 0028-4793 |
Popis: | Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation.We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse.TP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (P=0.004), owing to a high risk of relapse, and the presence of JAK2 mutations was associated with shorter survival than was the absence of JAK2 mutations (P=0.001), owing to a high risk of death without relapse. The adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens. By contrast, the adverse effect of RAS pathway mutations on the risk of relapse, as compared with the absence of RAS pathway mutations, was evident only with reduced-intensity conditioning (P0.001). In young adults, 4% of the patients had compound heterozygous mutations in the Shwachman-Diamond syndrome-associated SBDS gene with concurrent TP53 mutations and a poor prognosis. Mutations in the p53 regulator PPM1D were more common among patients with therapy-related MDS than those with primary MDS (15% vs. 3%, P0.001).Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen. (Funded by the Edward P. Evans Foundation and others.). |
Databáze: | OpenAIRE |
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