title: DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.
abstract: 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).
authors.affiliation: Department of Medicine, Hematology Oncology Division, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Sanne
authors.initials: S
authors.lastname: Lugthart
authors.forename: Yushan
authors.initials: Y
authors.lastname: Li
authors.forename: Claudia
authors.initials: C
authors.lastname: Erpelinck-Verschueren
authors.forename: Xutao
authors.initials: X
authors.lastname: Deng
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Schifano
authors.forename: James
authors.initials: J
authors.lastname: Booth
authors.forename: Wim
authors.initials: W
authors.lastname: van Putten
authors.forename: Lucy
authors.initials: L
authors.lastname: Skrabanek
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.forename: Madhu
authors.initials: M
authors.lastname: Mazumdar
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin