Landscape of TET2 mutations in acute myeloid leukemia

Abstract

We investigated ten --eleven translocation 2 (TET2) mutations in acute myeloid leukemia (AML), their correlation with other gene mutations and prognostic value. By deep-sequencing, 131 somatic TET2 mutations were identified in 87/318 (27.4%) patients. Of 87 mutated cases, 44 (50.6%) carried two mutations. TET2 mutations were concomitantly observed with mutations in NPM1, FLT3-ITD, FLT3-TKD, JAK2, RUNX1, CEBPA, CBL and KRAS. However, TET2 mutations rarely concomitantly occurred with IDH1mut or IDH2mut (2/251 or 0/184; P ¼ 0.046 and P ¼ 0.003, respectively). TET2 mutations were associated with normal karyotype AML (CN-AML) (62/206 (30.1%) CN-AML vs 20/107 (18.7%) aberrant karyotype; P ¼ 0.031), higher white blood cell count (mean 65.3 vs 40.3 Â 10 9 /l, P ¼ 0.023), lower platelet count (mean 68.6 vs 92.4 Â 10 9 /l, P ¼ 0.03) and higher age (67.5 vs 65.2 years, Po0.001). Survival analyses were restricted to de novo CN-AML patients (n ¼ 165) and showed inferior event-free survival (EFS) of TET2 mutations compared with TET2wt (median: 6.7 vs 18.7 months, P ¼ 0.009). This negative effect of TET2 mutation on EFS was particularly observed in patients p65 years (median: 8.9 months vs not reached (n.r.), P ¼ 0.027) as well as in patients of the European LeukemiaNet favorable-risk subgroup, that is, patients harboring mutated CEBPA and/or mutated NPM1 without FLT3-ITD (median: 10.3 vs 41.3 months, P ¼ 0.048). These data support a role for TET2 as an important prognostic biomarker in AML.

Clonal evolution in the transition from cutaneous disease to acute leukemia suggested by liquid biopsy in blastic plasmacytoid dendritic cell neoplasm

“…A high frequency of TET2 mutations was also suggested by a small targeted sequencing study (n=5) in which all cases showed changes to this gene 12543/60449 reads). The TET2 insertion has not previously been reported in BPDCN ( Figure 1E and Table 1) but has been found in myeloid diseases (MDS, AML and CMML) 10,11 . RHOA G17V has been found in the T-cell lymphoproliferative diseases, ATLL 12 and AITL 13 and also in 20% (3/15) cases of NK/T cell lymphoma 14 but has also not previously been reported in BPDCN.…”

Insights into cell ontogeny, age, and acute myeloid leukemia

“…TET2 mutations in adult AML commonly co-occur with other somatic mutations including NPM1, RARα, KIT, FLT3, RAS, MLL and C/EBPα [92][93][94][95][96]. ASXL1 mutations occur in adult AML (5-30%) more often in patients over 60 years (16%) than in patients 60 years and younger (3.2%).…”

The Impact of Molecular Genetic in Acute Myeloid Leukemias

“…TET2 mutations have been identified in approximately 30% of AML cases by deep sequencing [109], usually in combination with other molecular abnormalities, except for IDH1/IDH2 mutations with which they have been shown to be mutually exclusive [110]. It has been reported to occur in >10% of younger AML patients [110].…”

“…It has been reported to occur in >10% of younger AML patients [110]. When present in NPM1 mutated, FLT3-ITD wild-type disease (defined as a favorable risk group, according to European Leukemia Net classification), TET2 mutations confer a poor prognostic impact [26,109].…”