Significance of genetic variation at the glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase 1 detoxification genes in breast cancer development.

This work examined the role of constitutional genetic variation at the glutathione S-transferase M1 (GSTM1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) detoxification loci in breast cancer development. Methods included contrasting patterns of genetic variations at these loci between cases with breast cancer and healthy controls and assessing the association of genotypes with tumor characteristics. Participants were Caucasian women living in the Greater Philadelphia region, recruited from 1988 to 1994, with recently diagnosed women attending breast cancer clinics at Fox Chase Cancer Center (FCCC) and network affiliated hospitals as cases, and FCCC employees or women attending noncancer clinics as controls. The GSTM1 locus was determined for 402 cases and 238 controls, NQO1 for 346 cases and 235 controls. Results show that neither locus was associated with breast cancer occurrence, with the GSTM1 null genotype occurring at frequencies of 0.560 and 0.563 in cases and controls, respectively odds ratio (OR) 0.98, 0.95 confidence interval (CI) 0.70-1.38] and the NQO1 wild-type allele at frequencies of 0.808 and 0.845, respectively (OR 0.77, 0.95 CI 0.55-1.06). The GSTM1 null genotype, however, was significantly overrepresented among larger (T3 and T4) primary tumors (OR 7.61, 0.95 CI 1.05-333) and with the occurrence of axillary lymph node metastases (OR 1.62, 0.95 CI 0.98-2.69). NQO1 results revealed that homozygotes for the wild type allele were more likely to have ductal carcinoma and poor histologic grade when compared with individuals carrying one or two mutated alleles (OR 3.50, 0.95 CI 1.41-9.0, and OR 2.26, 0.95 CI 1.18-4.35 for histology type and grade, respectively). We conclude that while these loci are not associated with breast cancer occurrence, the GSTM1 locus is likely associated with tumor progression. NQO1 results suggest that different quinones (possibly estrogenic quinone metabolites) might affect the histological development of breast tumors.