Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci

Abstract

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P = 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P = 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P = 0.001) and MC1R asp294/asp294 (P = 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P = 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor.

Induction of the Phase 2 Response in Mouse and Human Skin by Sulforaphane-containing Broccoli Sprout Extracts

“…Similarly, NQO1-deficient mice are much more sensitive to skin carcinogenesis compared with their wild-type counterparts (18). In humans, an inverse association between NQO1-positive genotype and the number of cutaneous basal cell carcinomas has been observed (19), as well as higher sensitivity to UV-radiation-induced cutaneous damage in individuals homozygously deficient in GSTT1 and/or GSTM1 (20). Thus, both human polymorphisms of phase 2 enzymes and deletion of their genes in mice increase susceptibility to skin tumor development.…”

Coordinate Control of Expression of Nrf2-Modulated Genes in the Human Small Airway Epithelium Is Highly Responsive to Cigarette Smoking

“…For example, the NQO1 gene catalyzes the detoxification of quinones and stabilizes the tumor suppressor p53 protein (45,46). Additionally, NQO1-deficient individuals have a higher risk of developing leukemia (47,48) and other type of cancers (49,50). Another example is the family members of glutathione-Stransferases (GSTs) that catalyze the conjugation of reduced glutathione.…”

Catalog of 320 single nucleotide polymorphisms (SNPs) in 20 quinone oxidoreductase and sulfotransferase genes

“…Hence, differences in the quality and quantity of NQO enzymes are likely to have a significant influence on the susceptibility to various common diseases, including arteriosclerosis, hypertension, and diabetes mellitus, as well as cancer. In fact, a Pro203Ser amino-acid substitution in the NQO1 gene has been implicated as a factor influencing risk for lung cancer (Rosvold et al 1995;Chen et al 1999;Lin et al 1999), cutaneous basal cell carcinoma (Clairmont et al 1999), and urological malignancy (Schulz et al 1997). In addition, this change appears to be associated with risk for a subtype of colon cancer characterized by mutation at codon 12 of the K-ras gene (Lafuente et al 2000).…”