title: 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.
authors.affiliation: Institut für Physiologische Chemie 1, Heinrich Heine Universität, Postfach 101007, D-40001 Düsseldorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Clairmont
authors.forename: H
authors.initials: H
authors.lastname: Sies
authors.forename: S
authors.initials: S
authors.lastname: Ramachandran
authors.forename: J T
authors.initials: JT
authors.lastname: Lear
authors.forename: A G
authors.initials: AG
authors.lastname: Smith
authors.forename: B
authors.initials: B
authors.lastname: Bowers
authors.forename: P W
authors.initials: PW
authors.lastname: Jones
authors.forename: A A
authors.initials: AA
authors.lastname: Fryer
authors.forename: R C
authors.initials: RC
authors.lastname: Strange
mesh_terms: D000367:Age Factors; D000483:Alleles; D016010:Binomial Distribution; D002280:Basal Cell Carcinoma / Q000201:enzymology / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D015999:Multivariate Analysis; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012737:Sex Factors; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D016660:NAD(P)H Dehydrogenase (Quinone)