title: TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group.
abstract: OBJECTIVE
  The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2(mut)) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2(mut) in a large cohort of patients with AML in the context of other AML-associated aberrations.
  
  
  METHODS
  Samples from 783 younger adult patients with AML were analyzed for the presence of TET2(mut) (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome.
  
  
  RESULTS
  In total, 66 TET2(mut) were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2(mut) were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDH(mut)) that were almost mutually exclusive with TET2(mut) (P < .001). TET2(mut) were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2(mut)-associated biology. TET2(mut) did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2(mut) and/or IDH(mut) revealed shorter overall survival (P = .03), although this association was not independent from known risk factors.
  
  
  CONCLUSIONS
  TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.
authors.affiliation: Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.forename: Marianne
authors.initials: M
authors.lastname: Habdank
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.forename: Marie
authors.initials: M
authors.lastname: von Lilienfeld-Toal
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.forename: Heinz-August
authors.initials: HA
authors.lastname: Horst
authors.forename: Detlef
authors.initials: D
authors.lastname: Haase
authors.forename: Martin
authors.initials: M
authors.lastname: Bentz
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018570:Risk Assessment; D012720:Severity of Illness Index; D015996:Survival Rate; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human