DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.
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).
Figueroa
Maria E
ME
Department of Medicine, Hematology Oncology Division, Weill Cornell Medical College, New York, NY 10065, USA.
Lugthart
Sanne
S
Li
Yushan
Y
Erpelinck-Verschueren
Claudia
C
Deng
Xutao
X
Christos
Paul J
PJ
Schifano
Elizabeth
E
Booth
James
J
van Putten
Wim
W
Skrabanek
Lucy
L
Campagne
Fabien
F
Mazumdar
Madhu
M
Greally
John M
JM
Valk
Peter J M
PJ
Löwenberg
Bob
B
Delwel
Ruud
R
Melnick
Ari
A
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
D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin