DNA Methylation Signatures Identify Biologically Distinct Subtypes in Acute Myeloid Leukemia

By Maria E. Figueroa, S. Lugthart, Yushan Li, Claudia A. J. Erpelinck-Verschueren, Xutao Deng, P. Christos, E. Schifano, J. Booth, W. van Putten, Lucy Skrabanek and 7 more. Cancer Cell, 2010

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SUMMARY We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/25e086855e2fbb039d715d2149f454fba5f3ea9d

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Citations in the corpus

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia (2011, background): “AML represents a paradigm for understanding how complex patterns of cooperating genetic and epigenetic alterations lead to tumorigenesi”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Detailed genomic studies of the methylation landscapes of MPN and AML revealed core sets of genes that are differentially methylated between transformed cells and normal hematopoietic cells (17, 18).”
Therapeutic advances in acute myeloid leukemia. (2011, positive): “Further, unique AML subtypes were identified solely based on distinctive DNA methylation signatures even without a common molecular or cytogenetic abnormality and these were found to independently predict survival in AML.(57) Such subgroups may be candidates for demethylating therapies.”
DNA methylation presents distinct binding sites for human transcription factors (2013, background): “For example, recent DNA methylome studies in cancer have identified dynamic epigenetic changes, resulting in global reprogramming in gene expression (Jones and Baylin, 2007; Figueroa et al., 2010; Noushmehr et al., 2010).”
Biology, risk stratification, and therapy of pediatric acute leukemias: an update. (2011, methodology): “A 15-gene methylation classifier has been reported to have prognostic significance.(97)”
Breast cancer intrinsic subtype classification, clinical use and future trends. (2015, background): “A 15-gene methylation classifier was reported to be predictive of overall survival in AML [80].”
IDH mutation impairs histone demethylation and results in a block to cell differentiation (2012, methodology): “MassARRAY primer design was done as previously describe”
Low-level processing of Illumina Infinium DNA Methylation BeadArrays (2013, background): “As AML is a notoriously diverse disease with signiﬁcant epigenetic heterogeneity (14), the data allowed us to compare the ability of the various background-correction methods to minimize differences between platforms, without diminishing biological differences between patients.”
Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation (2010, methodology): “Themethylation status of genes included in the IDH1/2 epigenetic signature was examined in a series of 344 AMLs from Erasmus University Medical Center which were previously analyzed by HELP assays using the samemicroarray design (Figueroa et al., 2010).”
Functional normalization of 450k methylation array data improves replication in large cancer studies (2014, neutral): “Each sample was classified by TCGA according to the French-American-British (FAB) classification scheme [40], which proposes eight tumor subtypes, and methylation differences can be expected between the subtypes [41,42].”