Polymorphisms in human homeobox HLX1 and DNA repair RAD51 genes increase the risk of therapy-related acute myeloid leukemia

Blood. 2006 Dec 1;108(12):3916-8. doi: 10.1182/blood-2006-05-022921. Epub 2006 Aug 10.

Abstract

Studies of radiation-induced acute myeloid leukemia (AML) in mice suggest that the number of target stem cells is a risk factor, and the HLX1 homeobox gene, which is important for hematopoietic development, is a candidate gene. The distribution of the C/T-3' untranslated region (UTR) polymorphism in HLX1 in patients with AML and therapy-related AML (t-AML) compared with controls was therefore determined. The presence of the variant HLX1 allele significantly increases the risk of t-AML (OR = 3.36, 95% CI, 1.65-6.84). The DNA repair gene RAD51 (135G/C-5' UTR) polymorphism also increases t-AML risk, and when combined analysis was performed on both RAD51 and HLX1 variant alleles, a synergistic 9.5-fold increase (95% CI, 2.22-40.64) in the risk of t-AML was observed. We suggest that the HLX1 polymorphism has an effect on stem cell numbers, whereas an increased DNA repair capacity (RAD51) will suppress apoptosis, a genetic interaction that may increase the number of genomes at risk during cancer therapy.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Alleles
  • Animals
  • Apoptosis / genetics
  • DNA Repair* / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / chemically induced
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Acute / therapy
  • Male
  • Mice
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplasms, Second Primary / genetics*
  • Neoplasms, Second Primary / metabolism
  • Neoplasms, Second Primary / pathology
  • Neoplasms, Second Primary / therapy
  • Polymorphism, Single Nucleotide*
  • Rad51 Recombinase / genetics*
  • Rad51 Recombinase / metabolism
  • Risk Factors
  • Stem Cells / metabolism
  • Stem Cells / pathology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • 5' Untranslated Regions
  • HLX protein, human
  • Homeodomain Proteins
  • Neoplasm Proteins
  • Transcription Factors
  • RAD51 protein, human
  • Rad51 Recombinase