title: Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia.
abstract: The outcome of approximately 20% of patients with acute lymphoblastic leukemia (ALL) remains poor because of disease recurrence. We examined whether DNA methylation of cadherin superfamily genes is a useful biomarker for ALL relapse.
  
  
  
  We used Infinium Methylation 450K Arrays to assess genome-wide DNA methylation status. The methylation status of each individual gene was then determined by a combination of bisulfite restriction analysis and genome bisulfite sequencing. mRNA expression was evaluated by reverse-transcriptase PCR (RT-PCR) and quantitative real-time PCR.
  
  
  
  Cadherin superfamily genes including cadherin (CDH) 1, protocadherin (PCDH) 8, and PCDH17 were selected for analysis of methylation status. In 40 patient samples with B-cell precursor (BCP) ALL at diagnosis, the methylation frequencies of CDH1, PCDH8, and PCDH17 were 62.5, 55, and 30%, respectively. CDH1 and PCDH8 methylation was also detected in 80 and 20% of control bone marrow (BM) samples, respectively. On the contrary, PCDH17 was unmethylated in all control BM samples. There was a significant correlation between the methylation status of PCDH17 (but not CDH1 and PCDH8) and event-free survival or overall survival. Univariate and multivariate analyses showed that only PCDH17 methylation was associated with an increased risk for relapse and mortality in patients with BCP ALL.
  
  
  
  PCDH17 methylation at diagnosis was closely related to poor prognosis and thus could be used as a new biomarker to predict relapse in patients with BCP ALL.
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Thanh Nha
authors.initials: TN
authors.lastname: Uyen
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.|Department of Pediatric Hematology and Oncology, Nagano Children's Hospital, Azumino, Nagano, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakashita
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Lika'a Fasih Y
authors.initials: LF
authors.lastname: Al-Kzayer
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Nakazawa
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurata
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
mesh_terms: D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D000091363:Protocadherins; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; C529349:PCDH17 protein, human; C115816:PCDH8 protein, human; D000091363:Protocadherins
keywords: BCP ALL; DNA methylation; PCDH17; prognostic factors; relapse