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A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2009 Jun 15; Vol. 15 (12), pp. 4165-73. Date of Electronic Publication: 2009 Jun 09. - Publication Year :
- 2009
-
Abstract
- 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.<br />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.<br />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).<br />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.
- Subjects :
- Adult
Aged
Alleles
Breast Neoplasms genetics
Cohort Studies
Female
Genotype
Humans
Kaplan-Meier Estimate
Middle Aged
Mitochondria metabolism
Multivariate Analysis
Norway
Polymorphism, Single Nucleotide
Proportional Hazards Models
Regression Analysis
Survival Rate
United States
Antineoplastic Agents, Alkylating therapeutic use
Breast Neoplasms drug therapy
Breast Neoplasms mortality
Cyclophosphamide therapeutic use
Drug Resistance, Neoplasm genetics
Superoxide Dismutase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 15
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 19509150
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-09-0119