Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia

Jatinder K. Lamba, Xueyuan Cao, Susana C. Raimondi, Roya Rafiee, James R. Downing, Shi Lei, Tanja Gruber, Raul C. Ribeiro, Jeffrey E. Rubnitz, Stanley B. Pounds

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 multicenter 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.

Original languageEnglish (US)
Pages (from-to)26711-26723
Number of pages13
JournalOncotarget
Volume9
Issue number42
DOIs
StatePublished - Jun 1 2018

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Acute Myeloid Leukemia
Epigenomics
Pediatrics
Methylation
Clinical Trials
Residual Neoplasm
Gene Expression Profiling
DNA Methylation
Disease-Free Survival
Neoplasms
Genome
Recurrence
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology

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Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia. / Lamba, Jatinder K.; Cao, Xueyuan; Raimondi, Susana C.; Rafiee, Roya; Downing, James R.; Lei, Shi; Gruber, Tanja; Ribeiro, Raul C.; Rubnitz, Jeffrey E.; Pounds, Stanley B.

In: Oncotarget, Vol. 9, No. 42, 01.06.2018, p. 26711-26723.

Research output: Contribution to journalArticle

Lamba, JK, Cao, X, Raimondi, SC, Rafiee, R, Downing, JR, Lei, S, Gruber, T, Ribeiro, RC, Rubnitz, JE & Pounds, SB 2018, 'Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia', Oncotarget, vol. 9, no. 42, pp. 26711-26723. https://doi.org/10.18632/oncotarget.25475
Lamba, Jatinder K. ; Cao, Xueyuan ; Raimondi, Susana C. ; Rafiee, Roya ; Downing, James R. ; Lei, Shi ; Gruber, Tanja ; Ribeiro, Raul C. ; Rubnitz, Jeffrey E. ; Pounds, Stanley B. / Integrated epigenetic and genetic analysis identifies markers of prognostic significance in pediatric acute myeloid leukemia. In: Oncotarget. 2018 ; Vol. 9, No. 42. pp. 26711-26723.
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AU - Rafiee, Roya

AU - Downing, James R.

AU - Lei, Shi

AU - Gruber, Tanja

AU - Ribeiro, Raul C.

AU - Rubnitz, Jeffrey E.

AU - Pounds, Stanley B.

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AB - 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 multicenter 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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