title: Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies.
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.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis TN 38105, USA.
authors.forename: Javier G
authors.initials: JG
authors.lastname: Blanco
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Edick
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hancock
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.forename: Thierry
authors.initials: T
authors.lastname: Dervieux
authors.forename: Michael D
authors.initials: MD
authors.lastname: Amylon
authors.forename: Robert O
authors.initials: RO
authors.lastname: Bash
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Behm
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human