Jumpei Yamazaki1, Rodolphe Taby1, Jaroslav Jelinek1, Noel J M Raynal1, Matteo Cesaroni1, Sherry A Pierce1, Steven M Kornblau1, Carlos E Bueso-Ramos1, Farhad Ravandi1, Hagop M Kantarjian1, Jean-Pierre J Issa2. 1. Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX. 2. Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA (JY, JJ, NJMR, MC, JPJI); Department of Leukemia (JY, RT, JJ, NJMR, SAP, SMK, FR, HMK, JPJI) and Department of Hematopathology (CEBR), The University of Texas MD Anderson Cancer Center, Houston, TX. jpissa@temple.edu.
Abstract
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.
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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