Germline genomic variants associated with childhood acute lymphoblastic leukemia

Nat Genet. 2009 Sep;41(9):1001-5. doi: 10.1038/ng.432. Epub 2009 Aug 16.

Abstract

Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 x 10(-5)) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 x 10(-15), odds ratio (OR) = 1.91; rs10994982, P = 5.7 x 10(-9), OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 x 10(-5), OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n = 124 children with ALL; P = 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / therapeutic use
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 10
  • Chromosomes, Human, Pair 7
  • Cohort Studies
  • DNA-Binding Proteins / genetics
  • Dopa Decarboxylase / genetics
  • European Continental Ancestry Group / genetics
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome-Wide Association Study
  • Germ Cells*
  • Germ-Line Mutation
  • Haplotypes
  • Humans
  • Ikaros Transcription Factor / genetics
  • Linkage Disequilibrium
  • Methotrexate / metabolism
  • Methotrexate / therapeutic use
  • Odds Ratio
  • Oncogene Proteins, Fusion / genetics
  • Polyglutamic Acid / metabolism
  • Polymorphism, Single Nucleotide
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / classification*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Probability
  • Reproducibility of Results
  • Risk Factors
  • Trans-Activators
  • Transcription Factors / genetics

Substances

  • ARID5B protein, human
  • Antimetabolites, Antineoplastic
  • DNA-Binding Proteins
  • IKZF1 protein, human
  • MRTFA protein, human
  • Oncogene Proteins, Fusion
  • Trans-Activators
  • Transcription Factors
  • Ikaros Transcription Factor
  • Polyglutamic Acid
  • Dopa Decarboxylase
  • Methotrexate

Grant support