Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations

J Natl Cancer Inst. 2013 May 15;105(10):733-42. doi: 10.1093/jnci/djt042. Epub 2013 Mar 19.

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the incidence of ALL varies by ethnicity. Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined.

Methods: We performed a multiethnic genome-wide association study in 1605 children with ALL and 6661 control subjects after adjusting for population structure, with validation in three replication series of 845 case subjects and 4316 control subjects. Association was tested by two-sided logistic regression.

Results: A novel ALL susceptibility locus at 10p12.31-12.2 (BMI1-PIP4K2A, rs7088318, P = 1.1 × 10(-11)) was identified in the genome-wide association study, with independent replication in European Americans, African Americans, and Hispanic Americans (P = .001, .009, and .04, respectively). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. Associations at ARID5B, IKZF1, and BMI1-PIP4K2A variants were consistent across ethnicity, with multiple independent signals at IKZF1 and BMI1-PIP4K2A loci. The frequency of ARID5B and BMI1-PIP4K2A variants differed by ethnicity, in parallel with ethnic differences in ALL incidence. Suggestive evidence for modifying effects of age on genetic predisposition to ALL was also observed. ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at a ninefold (95% confidence interval = 6.9 to 11.8) higher ALL risk relative to those carrying zero to one risk allele at these four single nucleotide polymorphisms.

Conclusions: These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children and shed new light on ALL molecular etiology in diverse ancestry.

Publication types

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

MeSH terms

  • Adolescent
  • African Americans / genetics*
  • CCAAT-Enhancer-Binding Proteins / genetics
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 10 / genetics*
  • Chromosomes, Human, Pair 14 / genetics
  • Chromosomes, Human, Pair 7 / genetics
  • DNA-Binding Proteins / genetics
  • European Continental Ancestry Group / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hispanic Americans / genetics*
  • Humans
  • Ikaros Transcription Factor / genetics
  • Logistic Models
  • Male
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Neoplasm Proteins / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Polymorphism, Single Nucleotide*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / ethnology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Risk Assessment
  • Risk Factors
  • Transcription Factors / genetics

Substances

  • ARID5B protein, human
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • IKZF1 protein, human
  • Neoplasm Proteins
  • Transcription Factors
  • CEBPE protein, human
  • Ikaros Transcription Factor
  • PIP4K2A protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7