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

Robert CG Martin¹ , Jiyoung Ahn²^,3 , Susan A Nowell⁴ , David W Hein⁵ , Mark A Doll⁵ , Benjamin D Martini⁵ and Christine B Ambrosone³

¹Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA

²Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA

³Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York, USA

⁴Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, Arkansas, USA

⁵Department of Pharmacology and Toxicology, and the James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA

author email corresponding author email

Breast Cancer Research 2006, 8:R45doi:10.1186/bcr1532


Published:	19 July 2006

Abstract

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.