Association between manganese superoxide dismutase promoter gene polymorphism and breast cancer survival.

BACKGROUND: Manganese superoxide dismutase (MnSOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species, constituting a major cellular defense mechanism against agents that induce oxidative stress. A genetic polymorphism in the mitochondrial targeting sequence of this gene has been associated with increased cancer risk and survival in breast cancer. This base pair transition (-9 T > C) leads to a valine to alanine amino acid change in the mitochondrial targeting sequence. A polymorphism has also been identified in the proximal region of the promoter (-102 C>T) that alters the recognition sequence of the AP-2 transcription factor, leading to a reduction in transcriptional activity. The aim of our study was to investigate possible associations of the -102 C>T polymorphism with overall and relapse-free breast cancer survival in a hospital-based case-only study. MATERIALS AND METHODS: The relationship between the MnSOD -102 C>T polymorphism and survival was examined in a cohort of 291 women who received chemotherapy and/or radiotherapy for incident breast cancer. The MnSOD -102 C>T genotype was determined using a TaqMan allele discrimination assay. Patient survival was evaluated according to the MnSOD genotype using Kaplan-Meier survival functions. Hazard ratios were calculated from adjusted Cox proportional hazards modeling. All statistical tests were two-sided. RESULTS: In an evaluation of all women, there was a borderline significant reduction in recurrence-free survival with either one or both variant alleles (CT + TT) when compared with patients with wild-type alleles (CC) (odds ratio, 0.65; 95% confidence interval, 0.42-1.01). When the analysis was restricted to patients receiving radiation therapy, there was a significant reduction in relapse-free survival in women who were heterozygous for the MnSOD -102 genotype (relative risk, 0.40; 95% confidence interval, 0.18-0.86). Similarly, when the homozygous and heterozygous variant genotypes were combined, there remained a significant reduction in relapse-free survival in this group (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87). CONCLUSION: The MnSOD -102 variant allele appears to be associated with an improved recurrence-free survival in all patients, and more dramatically in subjects who received adjuvant radiation therapy.

The role of genetic variability in drug metabolism pathways in breast cancer prognosis.

Among patients receiving adjuvant therapy for breast cancer, there is variability in treatment outcomes, and it is unclear which patients will receive the most benefit from treatment and which will have better disease-free survival. To date, most studies of breast cancer prognosis have focused on tumor characteristics, but it is likely that pharmacogenetics, genetic variability in the metabolism of therapeutic agents, also plays a role in the prediction of survival. In this paper, we briefly discuss the metabolic pathways of drugs commonly used for the treatment of breast cancer (cyclophosphamide, doxorubicin, taxanes, tamoxifen and aromatase inhibitors) and describe the known genetic variants that may impact those pathways. Studies that have evaluated potential effects of these genetic variants on treatment outcomes are also discussed. It is likely that the application of pharmacogenetics, particularly in the setting of randomized clinical trials, will contribute to findings that may result in individualized therapeutic dosing.

Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients.

Tamoxifen has been a mainstay of adjuvant therapy for breast cancer for many years. We sought to determine if genetic variability in the tamoxifen metabolic pathway influenced overall survival in breast cancer patients treated with tamoxifen. We examined functional polymorphisms in CYP2D6, the P450 catalyzing the formation of active tamoxifen metabolites, and UGT2B15, a Phase II enzyme facilitating the elimination of active metabolite in a retrospective study of breast cancer patients. We also examined whether the combination of variant alleles in SULT1A1 and UGT2B15 had more of an impact on overall survival in tamoxifen-treated patients than when the genes were examined separately. We conducted a retrospective study using archived paraffin blocks for DNA extraction and data from pathology reports and hospital tumor registry data for information on clinical characteristics, treatment, and outcomes (162 patients receiving tamoxifen and 175 who did not). Genotypes for CYP2D6 and UGT2B15 were obtained and Cox proportional hazards modeling was performed. After adjusting for age, race, stage of disease at diagnosis, and hormone receptor status, we found no significant association between CYP2D6 genotype and overall survival in either group of breast cancer patients. Tamoxifen-treated patients with UGT2B15 high activity genotypes had increased risk of recurrence and poorer survival. When UGT2B15 and SULT1A1 'at-risk' alleles were combined, women with two variant alleles had significantly greater risk of recurrence and poorer survival than those with common alleles. These studies indicate that genetic variation in Phase II conjugating enzymes can influence the efficacy of tamoxifen therapy for breast cancer.

Gene-nutrient interactions in cancer etiology.

Relationships between dietary components and cancer risk are often unclear, and the results from epidemiologic studies are inconsistent. While some inconsistencies could be due to study design issues, we propose that genetic heterogeneity of study populations could mask associations. In this report, we review the literature regarding meat consumption and risk of colon, breast, and prostate cancers, particularly in relation to phenotypes and genotypes for enzymes that metabolize food-borne promutagens. The role of consumption of fruits and vegetables, as well as the role of genetic variants in oxidative stress genes, in the risk of breast cancer are also discussed.