Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies

Javier G. Blanco, Mathew J. Edick, Michael L. Hancock, Naomi J. Winick, Thierry Dervieux, Michael D. Amylon, Robert O. Bash, Frederick G. Behm, Bruce M. Camitta, Ching Hon Pui, Susana C. Raimondi, Mary V. Relling

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-ML) are serious complications that affect some patients after acute lymphoblastic leukemia (ALL) treatment. Genetic polymorphisms in the promoter of CYP3A4 (CYP3A4* 1B) and in NAD(P)H:quinone oxidoreductase (NQO1609C→T substitution) have been associated with the risk of t-ML. A polymorphism in CYP3A5 (CYP3A5* 3) affects CYP3A activity and the wild-type allele (CYP3A5* 1) is in partial linkage with the CYP3A4* 1B allele. We compared the genotype frequencies for the CYP3A5* 3, the CYP3A4* 1B and the NQO1609C→T substitution in 224 children with ALL who did not develop t-ML (controls) and in 53 children with ALL who did develop the complication. The allele frequencies differed significantly among whites, blacks and Hispanics (P < 0,001 for CYP3A5* 3, P < 0.001 for CYP3A4* 1B and P = 0.004 for NQO1609), thus we performed the comparisons between ALL controls and t-ML patients after accounting for race. We found no differences in the CYP3A4* 1B allele distribution between ALL controls and t-ML patients in whites (P = 0.339, 6.6% vs. 9.8%), blacks (P = 0.498, 93.8% vs. 87.5%) or Hispanics (P = 0.523, 39.1% vs. 25.0%). The frequencies for the NQO1609C→T allele did not differ between control and t-ML groups in whites (P = 0.191, 35.0% vs. 44.9%), blacks (P = 0.664, 37.5% vs. 37.5%) or Hispanics (P = 0.447, 65.2% vs. 50.0%). We found no differences between the control and t-ML group in the incidence of homozygous CYP3A5* 3 genotypes: 82.0% vs. 85.4% in whites (P = 0.403), 6.5% vs. 12.5% in blacks (P = 0.508), and 69.6% vs. 75.0% in Hispanics (P = 0.663). Our data do not support an association between common CYP3A4, NQO1 or CYP3A5 polymorphisms and the risk of t-ML in children treated for ALL.

Original languageEnglish (US)
Pages (from-to)605-611
Number of pages7
JournalPharmacogenetics
Volume12
Issue number8
DOIs
StatePublished - Nov 2002

Keywords

  • Acute lymphoblastic leukemia
  • Chemotherapy
  • Children
  • Therapy-related leukemia

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

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