Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia
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Jatinder K. Lamba1, Xueyuan Cao2, Susana C. Raimondi3, Roya Rafiee1, James R. Downing3, Lei Shi2, Tanja Gruber4, Raul C. Ribeiro4, Jeffrey E. Rubnitz4 and Stanley B. Pounds2
1Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA
2Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
3Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
4Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
Jatinder K. Lamba, email: [email protected]
Keywords: AML; methylation; pediatrics; leukemia
Received: February 16, 2018 Accepted: May 10, 2018 Published: June 01, 2018
Acute myeloid leukemia (AML) may be an epigenetically-driven malignancy because it harbors fewer genomic mutations than other cancers. In recent studies of AML in adults, DNA methylation patterns associate with clinical risk groups and prognosis. However, thorough evaluations of methylation in pediatric AML have not been done. Therefore, we performed an integrated analysis (IA) of the methylome and transcriptome with clinical outcome in 151 pediatric patients from the multi-center AML02 clinical trial discovery cohort. Intriguingly, reduced methylation and increased expression of DNMT3B was associated with worse clinical outcomes (IA p ≤ 10−5; q ≤ 0.002). In particular, greater DNMT3B expression associated with worse minimal residual disease (MRD; p < 10−5; q = 0.01), a greater rate of relapse or resistant disease (RR) (p = 0.00006; q = 0.06), and event-free survival (EFS; p = 0.00003; q = 0.04). Also, greater DNMT3B expression associated with greater genome-wide methylation burden (GWMB; R = 0.39; p = 10−6) and greater GWMB associated with worse clinical outcomes (IA p < 10−5). In an independent validation cohort of 132 similarly treated AAML0531 clinical trial patients, greater DNMT3B expression associated with greater GWMB, worse MRD, worse RR, and worse EFS (all p < 0.03); also, greater GWMB associated with worse MRD (p = 0.004) and EFS (p = 0.037). These results indicate that DNMT3B and GWMB may have a central role in the development and prognosis of pediatric AML.
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