title: RASSF1A hypermethylation in pretreatment serum DNA of neuroblastoma patients: a prognostic marker.
abstract: The tumour suppressor gene RASSF1A is known to be frequently silenced by promoter hypermethylation in neuroblastoma tumours. Here we explored the possible prognostic significance of aberrant promoter hypermethylation of RASSF1A in serum DNA samples of patients with neuroblastoma as a surrogate marker for circulating tumour cells. We analysed the methylation status of the RASSF1A gene in matched tumour and pretreatment serum DNA obtained from 68 neuroblastoma patients. Hypermethylation of RASSF1A in tumour samples was found in 64 patients (94%). In contrast, serum methylation of RASSF1A was observed in 17 patients (25%). Serum methylation of RASSF1A was found to be statistically associated with age > or =12 months at diagnosis (P=0.002), stage 4 (P<0.001) and MYCN amplification (P<0.001). The influence of serum RASSF1A methylation on prognosis was found to be comparable with that of the currently most reliable marker, MYCN amplification on univariate analysis (hazard ratio, 9.2; 95% confidence interval (CI), 2.8-30.1; P<0.001). In multivariate analysis of survival, methylation of RASSF1A in serum had a hazard ratio of 2.4 (95% CI, 0.6-9.2), although this association did not reach statistical significance (P=0.194). These findings show that the methylation status of RASSF1A in the serum of patients with neuroblastoma has the potential to become a prognostic predictor of outcome.
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan. amisawa@kuhp.kyoto-u.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Misawa
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Yagyu
authors.forename: K
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: T
authors.initials: T
authors.lastname: Iehara
authors.forename: T
authors.initials: T
authors.lastname: Sugimoto
authors.forename: H
authors.initials: H
authors.lastname: Hosoi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000097:blood*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D004247:DNA