TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study

Abstract

Purpose: 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).

Patients and 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.

Conclusion: 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.

Fig 1.

Localization of sequence variations in relation to the TET2 coding sequence. The cross-hatched areas mark the two evolutionarily conserved domains of TET2 (amino acids 1104 to 1478 and 1845 to 2002), and exon boundaries are shown as dashed red lines. Each arrow represents one of the 141 nonsynonymous sequence variations in TET2 found among 427 patients (except for known single-nucleotide polymorphisms, which were not considered). Nonsense and frame shift variations as well as variations affecting splice sites are shown in the upper part of the figure. Missense variations and in-frame insertions/deletions, which alter only one or two amino acids, are shown in the lower part. Variations that were absent in matched germline DNA and thus were proven to be somatically acquired mutations are shown by red arrows. Blue arrows represent changes that were also found in the corresponding germline sample, and black arrows represent sequence changes where corresponding germline DNA was not available. Nine of the missense changes (highlighted by asterisks) were located outside the conserved domains of TET2, and seven of them were present in the germline (two could not be tested). The nine patients harboring these changes were excluded from further analyses.

Fig 2.

(A) Disease-free survival and (B) overall survival of all patients with cytogenetically normal acute myeloid leukemia according to TET2 mutation status. (C) Disease-free survival and (D) overall survival of patients in the European LeukemiaNet (ELN) favorable-risk and intermediate-I–risk groups, according to TET2 mutation status. TET2-mut, mutated TET2; TET2-wt, wild-type TET2.