title: TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study.
abstract: OBJECTIVE
  To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML).
  
  
  METHODS
  Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays.
  
  
  RESULTS
  TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I-risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I-risk patients and found distinct mutation-associated microRNA signatures in both ELN groups.
  
  
  CONCLUSIONS
  TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, 1216 James Cancer Hospital, 300 West 10th Ave, Columbus, OH 43210, USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Dean
authors.initials: D
authors.lastname: Margeson
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: John
authors.initials: J
authors.lastname: Curfman
authors.forename: Kelsi B
authors.initials: KB
authors.lastname: Holland
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000032:analysis; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; C000716967:NPM1 protein, human; D011518:Proto-Oncogene Proteins; D000090243:Nucleophosmin; D049308:Dioxygenases; C541081:TET2 protein, human