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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 D545Tfs*10 frameshift loss of function - predicted TET2 D545Tfs*10 indicates a shift in the reading frame starting at amino acid 545 and terminating 10 residues downstream causing a premature truncation of the 2002 amino acid Tet2 protein (UniProt.org). D545Tfs*10 has not been characterized however, due to the effects of other truncation mutations downstream of D545Tfs*10 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 E1323* nonsense loss of function - predicted TET2 E1323* results in a premature truncation of the Tet2 protein at amino acid 1323 of 2002 (UniProt.org). E1323* has not been characterized however, due to the effects of other truncation mutations downstream of E1323* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 E320* nonsense loss of function - predicted TET2 E320* results in a premature truncation of the Tet2 protein at amino acid 320 of 2002 (UniProt.org). E320* has not been characterized however, due to the effects of other truncation mutations downstream of E320* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 I249fs frameshift loss of function - predicted TET2 I249fs results in a change in the amino acid sequence of the Tet2 protein beginning at aa 249 of 2002, likely resulting in premature truncation of the functional protein (UniProt.org). I249fs has not been characterized, however, due to the effects of other truncation mutations downstream of I249 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 K450* nonsense loss of function - predicted TET2 K450* results in a premature truncation of the Tet2 protein at amino acid 450 of 2002 (UniProt.org). K450* has not been characterized however, due to the effects of other truncation mutations downstream of K450* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q1191* nonsense loss of function - predicted TET2 Q1191* results in a premature truncation of the Tet2 protein at amino acid 1191 of 2002 (UniProt.org). Q1191* has not been characterized however, due to the effects of other truncation mutations downstream of Q1191* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q1414* nonsense loss of function - predicted TET2 Q1414* results in a premature truncation of the Tet2 protein at amino acid 1414 of 2002 (UniProt.org). Q1414* has not been characterized however, due to the effects of other truncation mutations downstream of Q1414* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q591* nonsense loss of function - predicted TET2 Q591* results in a premature truncation of the Tet2 protein at amino acid 591 of 2002 (UniProt.org). Q591* has not been characterized however, due to the effects of other truncation mutations downstream of Q591* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q642* nonsense loss of function - predicted TET2 Q642* results in a premature truncation of the Tet2 protein at amino acid 642 of 2002 (UniProt.org). Q642* has not been characterized however, due to the effects of other truncation mutations downstream of Q642* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q652* nonsense loss of function - predicted TET2 Q652* results in a premature truncation of the Tet2 protein at amino acid 652 of 2002 (UniProt.org). Q652* has not been characterized however, due to the effects of other truncation mutations downstream of Q652* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q690* nonsense loss of function - predicted TET2 Q690* results in a premature truncation of the Tet2 protein at amino acid 690 of 2002 (UniProt.org). Q690* has not been characterized however, due to the effects of other truncation mutations downstream of Q690* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q701* nonsense loss of function - predicted TET2 Q701* results in a premature truncation of the Tet2 protein at amino acid 701 of 2002 (UniProt.org). Q701* has not been characterized, however, due to the effects of other truncation mutations downstream of Q701 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q891fs frameshift loss of function - predicted TET2 Q891fs results in a change in the amino acid sequence of the Tet2 protein beginning at aa 891 of 2002, likely resulting in premature truncation of the functional protein (UniProt.org). Q891fs has not been characterized, however, due to the effects of other truncation mutations downstream of Q891 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q916* nonsense loss of function - predicted TET2 Q916* results in a premature truncation of the Tet2 protein at amino acid 916 of 2002 (UniProt.org). Q916* has not been characterized however, due to the effects of other truncation mutations downstream of Q916* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 Q958Rfs*49 frameshift loss of function - predicted TET2 Q958Rfs*49 indicates a shift in the reading frame starting at amino acid 958 and terminating 49 residues downstream causing a premature truncation of the 2002 amino acid Tet2 protein (UniProt.org). Q958Rfs*49 has not been characterized, however, due to the effects of other truncation mutations downstream of Q958 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 R1067* nonsense loss of function - predicted TET2 R1067* results in a premature truncation of the Tet2 protein at amino acid 1067 of 2002 (UniProt.org). R1067* has not been characterized however, due to the effects of other truncation mutations downstream of $1067* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 R1179Efs*47 frameshift loss of function - predicted TET2 R1179Efs*47 indicates a shift in the reading frame starting at amino acid 1179 and terminating 47 residues downstream causing a premature truncation of the 2002 amino acid Tet2 protein (UniProt.org). R1179Efs*47 has not been characterized, however, due to the effects of other truncation mutations downstream of R1179 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 R1404* nonsense loss of function - predicted TET2 R1404* results in a premature truncation of the Tet2 protein at amino acid 1404 of 2002 (UniProt.org). R1404* has not been characterized however, due to the effects of other truncation mutations downstream of R1404* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 R1465* nonsense loss of function - predicted TET2 R1465* results in a premature truncation of the Tet2 protein at amino acid 1465 of 2002 (UniProt.org). R1465* has not been characterized, however, due to the effects of other truncation mutations downstream of R1465 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
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.
TET2 S354* nonsense loss of function - predicted TET2 S354* results in a premature truncation of the Tet2 protein at amino acid 354 of 2002 (UniProt.org). S354* has not been characterized, however, due to the effects of other truncation mutations downstream of S354 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 S792* nonsense loss of function - predicted TET2 S792* results in a premature truncation of the Tet2 protein at amino acid 792 of 2002 (UniProt.org). S792* has not been characterized however, due to the effects of other truncation mutations downstream of S792* (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 S833Ffs*8 frameshift loss of function - predicted TET2 S833Ffs*8 indicates a shift in the reading frame starting at amino acid 833 and terminating 8 residues downstream causing a premature truncation of the 2002 amino acid Tet2 protein (UniProt.org). S833Ffs*8 has not been characterized, however, due to the effects of other truncation mutations downstream of S833 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 S835* nonsense loss of function - predicted TET2 S835* results in a premature truncation of the Tet2 protein at amino acid 835 of 2002 (UniProt.org). S835* has not been characterized, however, due to the effects of other truncation mutations downstream of S835 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 T1063Nfs*5 frameshift loss of function - predicted TET2 T1063Nfs*5 indicates a shift in the reading frame starting at amino acid 1063 and terminating 5 residues downstream causing a premature truncation of the 2002 amino acid Tet2 protein (UniProt.org). T1063Nfs*5 has not been characterized, however, due to the effects of other truncation mutations downstream of T1063 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 V1006Gfs*3 frameshift loss of function - predicted TET2 V1006Gfs*3 indicates a shift in the reading frame starting at amino acid 1006 and terminating 3 residues downstream causing a premature truncation of the 2002 amino acid Tet2 protein (UniProt.org). V1006Gfs*3 has not been characterized, however, due to the effects of other truncation mutations downstream of V1006 (PMID: 24994606), is predicted to lead to a loss of Tet2 protein function.
TET2 W1198* nonsense loss of function - predicted TET2 W1198* results in a premature truncation of the Tet2 protein at amino acid 1198 of 2002 (UniProt.org). W1198* has not been characterized however, due to the effects of other truncation mutations downstream of W1198* (PMID: 24994606), 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