Traver et al. (1992, 1997) characterized a polymorphism in NQO1, a C-to-T substitution at position 609 of NQO1 cDNA, which codes for a proline-to-serine change at residue 187 (P187S). In cells with a T/T genotype, NQO1 activity was not detected, and lack of activity corresponded to a lack of NQO1 protein.
Kelsey et al. (1997) found that the prevalence of the T/T genotype varied among ethnic groups from 4 to 20%, with the highest prevalence occurring in Asian populations.
Rothman et al. (1997) reported a case-control study of benzene-exposed workers in China showing an increased risk of hematotoxicity in individuals with the T/T NQO1 genotype. A protective role for NQO1 against benzene-derived quinones in bone marrow in situ required reconciling with the observation that freshly isolated bone marrow mononuclear and progenitor cells failed to express NQO1. Moran et al. (1999) showed that exposure to benzene metabolites does not induce NQO1 in individuals of the T/T genotype as it does in persons with the C/C genotype, and induces NQO1 to an intermediate degree in persons with the T/C genotype.
Synthetic antioxidants and extracts of cruciferous vegetables, including broccoli (Benson et al., 1980), are potent inducers of NQO1. Given the association between lack of NQO1 activity, benzene toxicity, and subsequent risk of benzene-induced leukemia, Smith (1999) decided to investigate the role of the 609C-to-T polymorphism in leukemia in general. With colleagues, he studied a series of 104 leukemia cases from the Chicago area, more than half of which represented myeloid leukemia secondary to chemotherapy. The mutant allele frequency was 1.4-fold higher than expected in the post-therapy AML cases and was 1.6-fold higher among patients with abnormalities in chromosomes 5 and/or 7. Zhang et al. (1998) had shown that benzene increases abnormalities in chromosomes 5 and 7 in exposed workers, and hydroquinone produces similar changes in cultured human cells (Zhang et al., 1998). Thus, lack of or lowered NQO1 activity may make individuals vulnerable to leukemia secondary to chemical exposure.
Fagerholm et al. (2008) found that homozygosity for the T/T genotype of NQO1 (NQO1*2, rs1800566T) strongly predicted poor survival among 2 independent series of women with breast cancer (114480) (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53 (191170)-aberrant tumors (P = 6.15 x 10(-5)).
