Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia

PLoS One. 2013 Jun 6;8(6):e65373. doi: 10.1371/journal.pone.0065373. Print 2013.

Abstract

Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

Design and methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • CpG Islands*
  • DNA Methylation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Male
  • Multivariate Analysis
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phenotype
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / diagnosis*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Prognosis
  • Promoter Regions, Genetic*
  • Survival Analysis

Substances

  • Neoplasm Proteins

Grants and funding

This work was supported by grants from the Swedish Cancer Society (GR), the Swedish Research Council (GR), the Swedish Childhood Cancer Foundation (GR, EF), the Medical Faculty, Umeå University (GR) and Lion’s Cancer Research Foundation, Umeå (SD, MBo, GR). The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007–2011 under grant agreement no. 200950 (GR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.