title: Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT.
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Bennett
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: R Coleman
authors.initials: RC
authors.lastname: Lindsley
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Brenton G
authors.initials: BG
authors.lastname: Mar
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Robert
authors.initials: R
authors.lastname: Soiffer
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Alyea
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ho
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Rafael Bejar and Bennett Caughey, University of California at San Diego, La Jolla, CA; Kristen E. Stevenson, R. Coleman Lindsley, Brenton G. Mar, David P. Steensma, Jerome Ritz, Robert Soiffer, Joseph H. Antin, Edwin Alyea, Philippe Armand, Vincent Ho, John Koreth, Donna Neuberg, and Corey S. Cutler, Dana-Farber Cancer Institute; R. Coleman Lindsley and Benjamin L. Ebert, Brigham and Women's Hospital, Harvard Medical School, Boston; Petar Stojanov, Gad Getz, and Benjamin L. Ebert, Broad Institute, Cambridge, MA. benjamin_ebert@dfci.harvard.edu.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000628:therapy*; D011379:Prognosis; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
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