Low NAD(P)H : quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that detoxifies quinon es and reduces oxidative stress. A cysteine-to-threonine (C-->T) substituti on polymorphism at nucleotide 609 of the NQO1 complementary DNA (NQO1 C609T ) results in a lowering of NQO1 activity. Individuals homozygous for this m utation have no NQO1 activity, and heterozygotes have low to intermediate a ctivity compared with people with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped for NQ O1 C609T. The majority of cases were diagnosed as acute myeloid leukemia (A ML) (n = 420); 67 as acute lymphoblastic leukemia (ALL); and 6 as other for ms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote + homozygous mutant) was significantly higher among total ac ute leukemia case subjects compared with their matched controls (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.17-1.89). Both ALL (OR = 1.93 ; 95% CI, 0.96-3.87) and AML case subjects (OR = 1.47; 95% CI, 1.13-1.90) e xhibited a higher frequency of low or null NQO1 genotypes than controls. Fo r de nova AML, the most significant effect of row or null NQO1 activity was observed among the 88 cases harboring translocations and inversions(OR = 2 .39; 95% CI, 1.34-4.27) and was especially high for those harboring inv(16) (OR = 8.13; 95% CI, 1.43-46.42). These findings were confirmed in a second group of 217 de nova AML cases with known cytogenetics. Thus, inheritance of NQO1 C609T confers an increased risk of de nova acute leukemia in adults , implicating quinones and related compounds that generate oxidative stress in producing acute leukemia.(Blood, 2001;97:1422-1426) (C) 2001 by The Ame rican Society of Hematology.