A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide.
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.
Glynn
Sharon A
SA
Laboratory of Human Carcinogenesis, Center for Cancer Research, Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4258, USA.
Boersma
Brenda J
BJ
Howe
Tiffany M
TM
Edvardsen
Hege
H
Geisler
Stephanie B
SB
Goodman
Julie E
JE
Ridnour
Lisa A
LA
Lønning
Per E
PE
Børresen-Dale
Anne-Lise
AL
Naume
Bjorn
B
Kristensen
Vessela N
VN
Chanock
Stephen J
SJ
Wink
David A
DA
Ambs
Stefan
S
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
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2