A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide

Sharon A. Glynn, Brenda J. Boersma, Tiffany M. Howe, Hege Edvardsen, Stephanie B. Geisler, Julie E. Goodman, Lisa A. Ridnour, Per E. Lønning, Anne Lise Børresen-Dale, Bjorn Naume, Vessela N. Kristensen, Stephen J. Chanock, David A. Wink, Stefan Ambs

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Manganese superoxide dismutase protects against oxidative damage and modulates the efficacy of chemotherapeutic drugs. A functional single-nucleotide polymorphismin codon16 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, 1.46-4.19), but not for patients without it (HR, 1.47; 95% CI, 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% CI, 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.

Original languageEnglish (US)
Pages (from-to)4165-4173
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number12
DOIs
StatePublished - Jun 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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