We determined that a single base change in the 5' flanking region of the CYP3A4 gene was associated with higher clinical stage and grade in men with prostate tumors. Our results suggest that mutations in the CYP3A4 gene may influence prostate carcinogenesis.

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 treatmentrelated leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatmentrelated 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.Second cancers are uncommon events occurring at a frequency of about 7% in survivors of primary malignant neoplasms (1). Although leukemias comprise a small fraction of second cancers (2), leukemias are the major second cancers that result from chemotherapy (3-6). There are two major forms of treatmentrelated leukemia, those with chromosome 5 and 7 monosomies induced by alkylating agents, and those with MLL gene translocations and other translocations related to DNA topoisomerase II inhibitors (7). Because only a minority of patients develop leukemia after chemotherapy, it has been suggested that differences in drug interactions with the host may be predisposing factors (8). Germ-line mutations in tumor-suppressor genes or genetic variation in drug metabolism are examples of host risk factors. Germ-line mutations in the NF-1 and p53 tumorsuppressor genes have been observed in alkylating agentassociated leukemias with chromosome 5 and 7 monosomies (9-12). Similar host risk factors for leukemias induced by DNA topoisomerase II inhibitors currently are unknown.We explored genetic variation in drug metabolism as a potential host risk factor. Distinct phase I and phase II pathways of drug metabolism comprise a protective mechanism against environmental toxins (13-15). Phase I metabolism by cytochrome P450 (CYP) enzymes converts many ...