title: DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes.
abstract: 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.
authors.affiliation: Department of Leukemia and Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
authors.forename: E
authors.initials: E
authors.lastname: Lin
authors.forename: Jianqin
authors.initials: J
authors.lastname: Shan
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.forename: Donald
authors.initials: D
authors.lastname: Berry
authors.forename: Saira
authors.initials: S
authors.lastname: Ahmed
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Hussain
authors.initials: H
authors.lastname: Saba
authors.forename: Eli
authors.initials: E
authors.lastname: Estey
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: 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