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Ref Type Journal Article
PMID (24994606)
Authors Aslanyan MG, Kroeze LI, Langemeijer SM, Koorenhof-Scheele TN, Massop M, van Hoogen P, Stevens-Linders E, van de Locht LT, Tonnissen E, van der Heijden A, da Silva-Coelho P, Cilloni D, Saglio G, Marie JP, Tang R, Labar B, Amadori S, Muus P, Willemze R, Marijt EW, de Witte T, van der Reijden BA, Suciu S, Jansen JH
Title Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.
Journal Annals of hematology
Vol 93
Issue 8
Date 2014 Aug
URL
Abstract Text We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis (p = 0.024). TET2 and IDH1/2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
TET2 R506* nonsense loss of function - predicted TET2 R506* results in a premature truncation of the Tet2 protein at amino acid 506 of 2002 (UniProt.org). R506* results in a loss of -5-hydroxymethylcytosine (5hmc) formation in cultured cells (PMID: 24994606), and therefore, is predicted to lead to a loss of Tet2 protein function.
TET2 S1758* nonsense loss of function - predicted TET2 S1758* results in a premature truncation of the Tet2 protein at amino acid 1758 of 2002 (UniProt.org). S1758* results in a loss of -5-hydroxymethylcytosine (5hmc) formation in cultured cells (PMID: 24994606), and therefore, is predicted to lead to a loss of Tet2 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TET2 mutant acute myeloid leukemia not applicable N/A Clinical Study Prognostic In multiple clinical studies, including a meta-analysis, TET2 mutations were associated with shorter overall survival in patients with acute myeloid leukemia (PMID: 24524305, PMID: 25412851, PMID: 24994606). 24524305 25412851 24994606