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- Title
Hypomethylation of TET2 Target Genes Identifies a Curable Subset of Acute Myeloid Leukemia.
- Authors
Yamazaki, Jumpei; Taby, Rodolphe; Jelinek, Jaroslav; Raynal, Noel J. M.; Cesaroni, Matteo; Pierce, Sherry A.; Kornblau, Steven M.; Bueso-Ramos, Carlos E.; Ravandi, Farhad; Kantarjian, Hagop M.; Issa, Jean-Pierre J.
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
DNA metabolism; DNA; PROGNOSIS; PROTEINS; RESEARCH funding; SULFITES; DNA-binding proteins; ACUTE myeloid leukemia; PREDICTIVE tests; DNA methylation; KAPLAN-Meier estimator; SEQUENCE analysis; ODDS ratio
- Publication
JNCI: Journal of the National Cancer Institute, 2016, Vol 108, Issue 2, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djv323