Prevalence of the inactivating C-609 -> T polymorphism in the NAD(P)H : quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia

NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less toxic hydroquinones and has been implicated in benzene-associated hema totoxicity. A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme activity in homozygous subjects, whereas those with 2 wild-t ype alleles have normal activity. The frequency of homozygosity for the mut ant allele among Caucasians and African Americans is 4% to 5% but is higher in Hispanics and Asians. Using an unambiguous polymerase chain reaction (P CR) method, we assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid l eukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All patients had th eir leukemia cells karyotyped. Eleven percent of the t-AML patients were ho mozygous and 41% were heterozygous for the NQO1 polymorphism; these proport ions were significantly higher than those expected in a population of the s ame ethnic mix (P = .036). Of the 45 leukemia patients who had clonal abnor malities of chromosomes 5 and/or 7, 7 (16%) were homozygous for the inactiv ating polymorphism, 17 (38%) were heterozygous, and 21 (47%) had 2 wild-typ e alleles for NQO1. Thus, NQO1 mutations were significantly increased compa red with the expected proportions: 5%, 34%, and 61%, respectively (P = .002 ). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygot es, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-t ype alleles. Among 33 patients with balanced translocations [14 involving b ands 11q23 or 21q22, 10 with inv(18) or t(15;17), and 9 with t(9;22)], ther e were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-typ e alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AM L patients, 6 were observed; 19 heterozygotes were expected, but 23 were ob served. The gene frequency for the inactivating polymorphism (0.31) was inc reased approximately 1.4-fold among the 56 t-AML patients. This increase wa s observed within each of the following overlapping cohorts of t-AML patien ts: the 43 who had received an alkylating agent, the 27 who had received a topoisomerase II inhibitor, and the 37 who had received any radiotherapy. T hus, the frequency of an inactivating polymorphism in NQO1 appears to be in creased in this cohort of myeloid leukemias, especially among those with t- AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygo tes (who are at risk for treatment-induced mutation or loss of the remainin g wild-type allele in their hematopoietic stem cells) may be particularly v ulnerable to leukemogenic changes induced by carcinogens. (C) 1999 by The A merican Society of Hematology.