TY - JOUR
T1 - Hypomethylation of TET2 Target Genes Identifies a Curable Subset of Acute Myeloid Leukemia
AU - Yamazaki, Jumpei
AU - Taby, Rodolphe
AU - Jelinek, Jaroslav
AU - Raynal, Noel J.M.
AU - Cesaroni, Matteo
AU - Pierce, Sherry A.
AU - Kornblau, Steven M.
AU - Bueso-Ramos, Carlos E.
AU - Ravandi, Farhad
AU - Kantarjian, Hagop M.
AU - Issa, Jean Pierre J.
N1 - Publisher Copyright:
© 2015 The Author 2015.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Background: Acute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification. Methods: We used bisulfite pyrosequencing to analyze the methylation status of four tet2-DMCs (SP140, MCCC1, EHMT1, and MTSS1) in a test group of 94 consecutive patients and a validation group of 92 consecutive patients treated with cytarabine-based chemotherapy. Data were analyzed with hierarchical clustering, Cox proportional hazards regression, and Kaplan-Meier analyses. All statistical tests were two-sided. Results: In the test cohort, hierarchical clustering analysis identified low levels of tet2-DMC methylation in 31 of 94 (33%) cases, and these had markedly longer overall survival (median survival 72+ vs 14 months, P =. 002). Similar results were seen in the validation cohort. tet2-DMC-low status was shown to be an independent predictor of overall survival (hazard ratio = 0.29, P =. 0002). In The Cancer Genome Atlas (TCGA) dataset where DNA methylation was analyzed by a different platform, tet2-DMC-low methylation was also associated with improved outcome (median survival = 55 vs 15 months, P =. 0003) and was a better predictor of survival than mutations in TET2, IDH1, or IDH2, individually or combined. Conclusions: Low levels of tet2-DMC methylation define a subgroup of AML that is highly curable and cannot be identified solely by genetic and cytogenetic analyses.
AB - Background: Acute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification. Methods: We used bisulfite pyrosequencing to analyze the methylation status of four tet2-DMCs (SP140, MCCC1, EHMT1, and MTSS1) in a test group of 94 consecutive patients and a validation group of 92 consecutive patients treated with cytarabine-based chemotherapy. Data were analyzed with hierarchical clustering, Cox proportional hazards regression, and Kaplan-Meier analyses. All statistical tests were two-sided. Results: In the test cohort, hierarchical clustering analysis identified low levels of tet2-DMC methylation in 31 of 94 (33%) cases, and these had markedly longer overall survival (median survival 72+ vs 14 months, P =. 002). Similar results were seen in the validation cohort. tet2-DMC-low status was shown to be an independent predictor of overall survival (hazard ratio = 0.29, P =. 0002). In The Cancer Genome Atlas (TCGA) dataset where DNA methylation was analyzed by a different platform, tet2-DMC-low methylation was also associated with improved outcome (median survival = 55 vs 15 months, P =. 0003) and was a better predictor of survival than mutations in TET2, IDH1, or IDH2, individually or combined. Conclusions: Low levels of tet2-DMC methylation define a subgroup of AML that is highly curable and cannot be identified solely by genetic and cytogenetic analyses.
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U2 - 10.1093/jnci/djv323
DO - 10.1093/jnci/djv323
M3 - Article
C2 - 26568194
AN - SCOPUS:84962495141
SN - 0027-8874
VL - 108
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 2
M1 - djv323
ER -