title: TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla, CA;
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Allegra
authors.initials: A
authors.lastname: Lord
authors.affiliation: Department of Biostatistics and Computational Biology and.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.affiliation: Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla, CA;
authors.forename: Albert
authors.initials: A
authors.lastname: Pérez-Ladaga
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
authors.forename: Jacques
authors.initials: J
authors.lastname: Zaneveld
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla, CA;
authors.forename: Bennett
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; and.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; and.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Biostatistics and Computational Biology and.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Medical Oncology, Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; and.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000368:Aged; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D016026:Bone Marrow Transplantation / Q000379:methods; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000235:genetics*; D000077209:Decitabine; D049308:Dioxygenases; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D018345:Mice, Knockout; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D018183:Transplantation Chimera / Q000235:genetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D049308:Dioxygenases; C541081:TET2 protein, human; D015254:DNA Modification Methylases; D001374:Azacitidine