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Analysis of Genetic Polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese Patients with Therapy-related Leukemia/Myelodysplastic Syndrome and de novo Acute Myeloid Leukemia¹

Department of Infectious Diseases [T. N., H. K.], The First Department of Internal Medicine [K. T., T. Y., H. S.], Nagoya University School of Medicine, Nagoya 466-8560, Japan; Laboratory of Chemotherapy, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan [M. S.]; Department of Hematology, National Kyushu Cancer Center, Fukuoka 811-1395, Japan [N. U.]; Department of Medicine, Fujita Health University, School of Medicine, Toyowake 470-1192, Japan [T. I.]; The Second Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan [A. U.]; Department of Hematology, Kanagawa Cancer Center, Yokohama 241-0815, Japan [A. M.]; Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan [I. J.]; Department of Cancer Cytogenetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan [N. K.]; Transfusion Medicine, School of Medicine, Kagawa Medical School, Kagawa 761-0793, Japan [Y. Ku.]; The Fifth Department of Internal Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan [H. N.]; The Second Department of Medicine [C. S.], and The Third Department of Medicine [S. H.], Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; Department of Medicine, Japanese Red Cross, Nagoya First Hospital, Nagoya 453-8511, Japan [Y. Ko.]; The Second Department of Internal Medicine, Nagoya City University Medical School, Nagoya 467-8601, Japan [R. U.]; Department of Epidemiology and Biostatistics, University of California San Francisco, California 94143-0560 [J. W.]; and Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan [R.O.]

Several genetic polymorphisms in metabolic activation or detoxification enzymes have been associated with susceptibility to therapy-related leukemia and myelodysplastic leukemia (TRL/MDS). We analyzed gene polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-tranferase (GST)-M1 and -T1, and CYP3A4, the enzymes of which are capable of metabolizing anticancer drugs, in 58 patients with TRL/MDS and in 411 patients with de novo acute myeloid leukemia (AML). Homozygous Ser/Ser genotype of NQO1 at codon 187, causing loss of function, was more frequent in the patients with TRL/MDS (14 of 58, 24.1%; OR = 2.62) than in those with de novo AML (64 of 411, 15.6%), and control (16 of 150, 10.6%; P = 0.002). Allelic frequencies of NQO1 were different between TRL/MDS and de novo AML (P = 0.01). In GST-M1 and -T1, the incidence of homologous deletion was similar among the three groups. The polymorphism of the 5' promoter region of CYP3A4 was not found in persons of Japanese ethnicity. These results suggest that the NQO1 polymorphism is significantly associated with the genetic risk of TRL/MDS.

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