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Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation.

ABSTRACT: Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known.We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MDS genes.Mutations were identified in 92% of patients, most frequently in the ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) genes. In univariable analyses, only TP53 mutations were associated with shorter overall (OS; hazard ratio [HR], 3.74; P < .001) and progression-free survival (HR, 3.97; P < .001). After adjustment for clinical variables associated with these end points, mutations in TP53 (HR, 2.30; P = .027), TET2 (HR, 2.40; P = .033), and DNMT3A (HR, 2.08; P = .049) were associated with decreased OS. In multivariable analysis including clinical variables, complex karyotype status, and candidate genes, mutations in TP53 (HR, 4.22; P ? .001) and TET2 (HR, 1.68; P = .037) were each independently associated with shorter OS. Nearly one half of patients (46%) carried a mutation in TP53, DNMT3A, or TET2 and accounted for 64% of deaths. Three-year OS in patients without these mutations was 59% (95% CI, 43% to 72%), versus 19% (95% CI, 9% to 33%) in patients with these mutations.Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT.

SUBMITTER: Bejar R

PROVIDER: S-EPMC4207878 | biostudies-other | 2014 Sep

REPOSITORIES: biostudies-other

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Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation.

Bejar Rafael R Stevenson Kristen E KE Caughey Bennett B Lindsley R Coleman RC Mar Brenton G BG Stojanov Petar P Getz Gad G Steensma David P DP Ritz Jerome J Soiffer Robert R Antin Joseph H JH Alyea Edwin E Armand Philippe P Ho Vincent V Koreth John J Neuberg Donna D Cutler Corey S CS Ebert Benjamin L BL

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20140804 25

<h4>Purpose</h4>Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known.<h4>Patients and methods</h4>We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MD ...[more]

PMID: 25092778

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Project description: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 (P<0.001 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 (P<0.001). 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%, P<0.001).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.).

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Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation.

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Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation.

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