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Ref Type Journal Article
PMID (25224413)
Authors Bejar R, Lord A, Stevenson K, Bar-Natan M, Perez-Ladaga A, Zaneveld J, Wang H, Caughey B, Stojanov P, Getz G, Garcia-Manero G, Kantarjian H, Chen R, Stone RM, Neuberg D, Steensma DP, Ebert BL
Title TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients.
Journal Blood
Vol 124
Issue 17
Date 2014 Oct 23
URL
Abstract Text Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ASXL1 wild-type TET2 mut myelodysplastic/myeloproliferative neoplasm sensitive Azacitidine Clinical Study - Cohort Actionable In a clinical study, myelodysplastic syndrome patients carrying TET2 mutations and wild-type ASXL1 demonstrated an increased response to treatment with the DNA hypomethylating agents Dacogen (decitabine) or Vidaza (azacitidine) compared to patients with other mutational profiles (65% vs. 44%; OR 2.37, P=0.49) (PMID: 25224413). 25224413
ASXL1 wild-type TET2 mut myelodysplastic/myeloproliferative neoplasm sensitive Decitabine Clinical Study - Cohort Actionable In a clinical study, myelodysplastic syndrome patients carrying TET2 mutations and wild-type ASXL1 demonstrated an increased response to treatment with the DNA hypomethylating agents Dacogen (decitabine) or Vidaza (azacitidine) compared to patients with other mutational profiles (65% vs. 44%; OR 2.37, P=0.49) (PMID: 25224413). 25224413