A Mitochondrial Target Sequence Polymorphism in Manganese Superoxide Dismutase Predicts Inferior Survival in Breast Cancer Patients Treated with Cyclophosphamide

作者：Glynn Sharon A; Boersma Brenda J; Howe Tiffany M; Edvardsen Hege; Geisler Stephanie B; Goodman Julie E; Ridnour Lisa A; Lonning Per E; Borresen Dale Anne Lise; Naume Bjorn; Kristensen Vessela N; Chanock Stephen J; Wink David A; Ambs Stefan^*

来源：Clinical Cancer Research, 2009, 15(12): 4165-4173.

DOI：10.1158/1078-0432.CCR-09-0119

Purpose: Manganese superoxide dismutase protects against oxidative damage and modulates the efficacy of chemotherapeutic drugs. A functional single-nucleotide polymorphism in codon 16 of SOD2 (rs4880), which encodes manganese superoxide dismutase, results in a substitution of valine by alanine (Val16Ala). We hypothesized that this single-nucleotide polymorphism affects breast cancer survival of patients receiving chemotherapy.
Experimental Design: Two patient populations from the United States (n = 248) and Norway (n = 340) were genotyped for Val16Ala. Kaplan-Meier survival and Cox proportional hazards regression analyses were used to examine the relationship between Val16Ala and disease-specific survival.
Results: Val16Ala was significantly associated with breast cancer outcome in both patient populations. Carriers of the Ala allele had inferior survival rates in the multivariate analysis [hazard ratio (HR), 2.44 and 95% confidence interval (95% CI), 1.11-5.37 in U.S. cohort; HR, 1.91 and 95% CI, 1.06-3.45 in Norway cohort for Ala/Ala versus Val/Val]. In an analysis of the combined cohorts, this association was significant for patients receiving adjuvant therapy (HR, 2.47; 95% CI, 1,464.19), but not for patients without it (HR, 1.47; 95% Cl, 0.57-3.74). After further stratification by type of chemotherapy, the effect of the Ala allele was mostly restricted to cyclophosphamide-containing chemotherapy regimens (HR, 22.0; 95% Cl, 5.22-92.9; Ala/Ala versus Val/Val).
Conclusion: The Val16Ala polymorphism affects survival of patients receiving cyclophosphamide-containing chemotherapy. The findings provide the first evidence pointing toward a mechanism for cyclophosphamide resistance in breast cancer patients.

• 出版日期2009-6-15
• 单位河北医科大学