title: DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia.
abstract: Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL.
  
  
  
  Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype.
  
  
  
  Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y ) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD ≥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group.
  
  
  
  CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Borssén
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Haider
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Landfors
authors.affiliation: Department of Clinical Sciences and Pediatrics, Umeå University, Umeå, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Norén-Nyström
authors.affiliation: Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: Department of Paediatrics, University Hospital of Trondheim, Norway.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Åsberg
authors.affiliation: Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kanerva
authors.affiliation: Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hans O
authors.initials: HO
authors.lastname: Madsen
authors.affiliation: Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Marquart
authors.affiliation: Department of Woman and Child health, Karolinska Institute, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Hultdin
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå, Sweden.|Department of Paediatrics, University Hospital of Trondheim, Norway.
authors.forename: Sofie
authors.initials: S
authors.lastname: Degerman
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D018365:Neoplasm, Residual; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm
keywords: DNA methylation; MRD; T-ALL; WBC; childhood leukemia; prognosis