DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes.
OBJECTIVE
The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS.


METHODS
We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome.


RESULTS
In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses.


CONCLUSIONS
DNA methylation predicts overall and progression-free survival in MDS.
Shen
Lanlan
L
Department of Leukemia and Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Kantarjian
Hagop
H
Guo
Yi
Y
Lin
E
E
Shan
Jianqin
J
Huang
Xuelin
X
Berry
Donald
D
Ahmed
Saira
S
Zhu
Wei
W
Pierce
Sherry
S
Kondo
Yutaka
Y
Oki
Yasuhiro
Y
Jelinek
Jaroslav
J
Saba
Hussain
H
Estey
Eli
E
Issa
Jean-Pierre J
JP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017326:Clinical Trials, Phase III as Topic; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000401:mortality* / Q000628:therapy*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult