title: Stronger prognostic power of the CpG island methylator phenotype than methylation of individual genes in neuroblastomas.
abstract: OBJECTIVE
  The CpG island methylator phenotype is strongly associated with poor survival in neuroblastomas. Neuroblastomas with the CpG island methylator phenotype include almost all neuroblastomas with MYCN amplification, and, even among neuroblastomas without MYCN amplification, have worse prognosis. At the same time, methylation of individual tumor-suppressor genes is also reported to be associated with poor survival. The purpose of this study was to compare the prognostic power of the CpG island methylator phenotype with that of methylation of individual genes.
  
  
  METHODS
  Methylation-specific polymerase chain reaction was performed for five individual genes (CASP8, EMP3, HOXA9, NR1I2 and CD44) in 140 Japanese and 152 German neuroblastomas. Kaplan-Meier analysis and log-rank tests were conducted to compare the survival between groups defined by methylation status.
  
  
  RESULTS
  Among the five individual genes, only CASP8 methylation had a significant association with poor overall survival both in Japanese (hazard ratio = 3.1; 95% confidence interval = 1.5-6.4; P = 0.002) and German (hazard ratio = 4.8; 95% confidence interval = 2.1-11; P = 0.0002) neuroblastomas. HOXA9 and NR1I2 methylation were associated with poor survival only in German neuroblastomas. On the other hand, the CpG island methylator phenotype had a strong and consistent association in Japanese (hazard ratio = 22; 95% confidence interval = 5.3-93; P = 1.5 × 10(-5)) and German (hazard ratio = 9.5; 95% confidence interval = 3.2-28; P = 4.7 × 10(-5)) neuroblastomas.
  
  
  CONCLUSIONS
  The CpG island methylator phenotype is likely to have stronger prognostic power than methylation of individual genes in neuroblastomas.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Asada
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.forename: Manfred
authors.initials: M
authors.lastname: Schwab
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D044466:Asian People / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics; D016001:Confidence Intervals; D018899:CpG Islands; D019175:DNA Methylation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008562:Membrane Glycoproteins / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality*; D011237:Predictive Value of Tests; D000077297:Pregnane X Receptor; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011987:Receptors, Steroid / Q000235:genetics
chemical_list: C497483:CD44 protein, human; C485157:EMP3 protein, human; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C097899:homeobox protein HOXA9; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: CIMP; methylation; neuroblastoma; poor survival