title: Genetic variants modify susceptibility to leukemia in infants: a Children's Oncology Group report.
abstract: BACKGROUND
  The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE.
  
  
  METHODS
  We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements.
  
  
  RESULTS
  Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633).
  
  
  CONCLUSIONS
  IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. rossx014@umn.edu
authors.forename: Julie A
authors.initials: JA
authors.lastname: Ross
authors.forename: Amy M
authors.initials: AM
authors.lastname: Linabery
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Blommer
authors.forename: Erica K
authors.initials: EK
authors.lastname: Langer
authors.forename: Logan G
authors.initials: LG
authors.lastname: Spector
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hilden
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Radloff
authors.forename: Richard L
authors.initials: RL
authors.lastname: Tower
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
mesh_terms: D002648:Child; D020022:Genetic Predisposition to Disease; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: C497239:IKZF1 protein, human; C497422:KMT2A protein, human; D051740:Ikaros Transcription Factor; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase