title: Association of CYP3A4 genotype with treatment-related leukemia.
abstract: Epipodophyllotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment-related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0. 016, FET). This relationship remained significant when 19 treatment-related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Felix
authors.forename: A H
authors.initials: AH
authors.lastname: Walker
authors.forename: B J
authors.initials: BJ
authors.lastname: Lange
authors.forename: T M
authors.initials: TM
authors.lastname: Williams
authors.forename: N J
authors.initials: NJ
authors.lastname: Winick
authors.forename: N K
authors.initials: NK
authors.lastname: Cheung
authors.forename: B D
authors.initials: BD
authors.lastname: Lovett
authors.forename: P C
authors.initials: PC
authors.lastname: Nowell
authors.forename: I A
authors.initials: IA
authors.lastname: Blair
authors.forename: T R
authors.initials: TR
authors.lastname: Rebbeck
mesh_terms: D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000139:chemically induced* / Q000145:classification / Q000235:genetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein; D009369:Neoplasms / Q000188:drug therapy; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics*; D010641:Phenotype; D011034:Podophyllotoxin / Q000009:adverse effects*; D011519:Proto-Oncogenes; D044469:Racial Groups; D014157:Transcription Factors; D014481:United States
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011495:Histone-Lysine N-Methyltransferase; D011034:Podophyllotoxin