TET2 Mutations in Acute Myeloid Leukemia (AML): Results From a Comprehensive Genetic and Clinical Analysis of the AML Study Group

• Published in: Journal of clinical oncology Vol. 30; no. 12; pp. 1350 - 1357
• Main Authors: GAIDZIK, Verena I, PASCHKA, Peter, BENTZ, Martin, GÖTZE, Katharina, DÖHNER, Hartmut, SCHLENK, Richard F, BULLINGER, Lars, DÖHNER, Konstanze, SPÄTH, Daniela, HABDANK, Marianne, KÖHNE, Claus-Henning, GERMING, Ulrich, VON LILIENFELD-TOAL, Marie, HELD, Gerhard, HORST, Heinz-August, HAASE, Detlef
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.04.2012
• Subjects: Acute myeloid leukemia; Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Biological and medical sciences; Combined Modality Therapy; Cytogenetic Analysis; Data processing; DNA Mutational Analysis; DNA-Binding Proteins - genetics; Exons; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic analysis; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation - methods; Humans; Isocitrate dehydrogenase; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Mutation; Odds Ratio; Oncogenes; Prognosis; Proportional Hazards Models; Prospective Studies; Proto-Oncogene Proteins - genetics; Risk Assessment; Risk factors; Severity of Illness Index; Survival; Survival Rate; Transplantation, Homologous; Treatment Outcome; Tumors; Young Adult; TET2 gene; Acute myelogenous leukemia; Cancerology; Genetics; Malignant hemopathy; Mutation; Cancer; Tumor suppressor gene
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2011.39.2886

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. 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. 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. 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.