title: A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4258, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Glynn
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Boersma
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Howe
authors.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Geisler
authors.forename: Julie E
authors.initials: JE
authors.lastname: Goodman
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Per E
authors.initials: PE
authors.lastname: Lønning
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Bjorn
authors.initials: B
authors.lastname: Naume
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D015999:Multivariate Analysis; D009664:Norway; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012044:Regression Analysis; D013482:Superoxide Dismutase / Q000235:genetics*; D015996:Survival Rate; D014481:United States; D000099156:Superoxide Dismutase 2
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2