Association of CYP 3 A 4 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 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 ...

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

“…These results demonstrate that, in Brazilians, CYP3A4*1B and CYP3A4*1A have a peculiar distribution. Although many studies have connected CYP3A4 genotypes with ethnicity (36,40,41,(46)(47)(48), in this study the genotype distribution revealed no correlation with patient skin color. Besides this, it was observed that the GG genotype was twice as common in non-white people (66.7%).…”

“…Clinical research (47) and in vitro functional analysis (25,48) generated controversial results concerning the affects of carrying CYP3A4-V. Studies of patients with the wild-type genotype (CYP3A*1A or CYP3A4-W) found that these individuals may be at an increased risk of treatmentrelated leukemia. The authors suggested that it may be a result of epipodophyllotoxin and other chemotherapeutic agent metabolism by CYP3A4.…”

“…The authors suggested that it may be a result of epipodophyllotoxin and other chemotherapeutic agent metabolism by CYP3A4. In this way, CYP3A4-V may damage the metabolism of anticancer drugs, reducing the production of potentially DNA-damaging reactive intermediates (47). Beyond the suggested roles in cancer response and TB immune response, the CYP3A4 gene may be explored in approaches for the prediction of therapy response in AIDS and TB, since CYP3A4 demonstrates a role in the metabolism of anti-HIV and anti-TB drugs (2)(3)(4)(5)(6)(7)(8).…”

Polymorphisms of drug‐metabolizing enzymes and risk of childhood acute lymphoblastic leukemia

“…CYP 1A1 variants, i.e., CYP 1A1*2A and *2B, have been shown to have increased activity and to be a genetic risk factor in certain types of cancer [7]. CYP 3A4*1B, the promotor variant of CYP 3A4, is also known to be associated with the risk of therapyrelated leukemia in childhood ALL with MLL rearrangement [8]. Recently, genetic polymorphisms and the expression of CYP 3A5 have been described [5].…”

Secondary hematopoietic malignancies in survivors of childhood cancer

“…For example, the presence of certain polymorphisms in detoxifying enzymes is associated with increased risk of secondary AML. 12,13 Most previous studies have analyzed all types of secondary malignancies, 14,15 but there are few comprehensive large-scale studies specifically on secondary hematological malignancies. Furthermore, most reports on secondary hematological malignancies focus on second leukemias only.…”