Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia.
BACKGROUND
In patients with acute myeloid leukemia (AML), the presence or absence of recurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the current classification system does not fully reflect the molecular heterogeneity of the disease, and treatment stratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype.


METHODS
We used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normal karyotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups with distinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novel supervised learning algorithm to devise a gene-expression-based clinical-outcome predictor, which we then tested using an independent validation group comprising the 57 remaining patients.


RESULTS
Unsupervised analysis identified new molecular subtypes of AML, including two prognostically relevant subgroups in AML with a normal karyotype. Using the supervised learning algorithm, we constructed an optimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patients in the independent validation group (P=0.006), including the subgroup of patients with AML with a normal karyotype (P=0.046). In multivariate analysis, the gene-expression predictor was a strong independent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P<0.001).


CONCLUSIONS
The use of gene-expression profiling improves the molecular classification of adult AML.
Bullinger
Lars
L
Department of Pathology, Stanford University, Stanford, Calif, USA.
Döhner
Konstanze
K
Bair
Eric
E
Fröhling
Stefan
S
Schlenk
Richard F
RF
Tibshirani
Robert
R
Döhner
Hartmut
H
Pollack
Jonathan R
JR
D000208:Acute Disease; D000328:Adult; D000465:Algorithms; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000145:classification / Q000235:genetics* / Q000401:mortality; D015999:Multivariate Analysis; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods; D016019:Survival Analysis