Glynn Sharon A, Boersma Brenda J, Howe Tiffany M, Edvardsen Hege, Geisler Stephanie B, Goodman Julie E, Ridnour Lisa A, Lønning Per E, Børresen-Dale Anne-Lise, Naume Bjorn, Kristensen Vessela N, Chanock Stephen J, Wink David A, Ambs Stefan
Laboratory of Human Carcinogenesis, Center for Cancer Research, Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4258, USA.
Clin Cancer Res. 2009 Jun 15;15(12):4165-73. doi: 10.1158/1078-0432.CCR-09-0119. Epub 2009 Jun 9.
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.
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.
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).
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.
锰超氧化物歧化酶可防止氧化损伤并调节化疗药物的疗效。编码锰超氧化物歧化酶的SOD2第16密码子（rs4880）处的功能性单核苷酸多态性导致缬氨酸被丙氨酸取代（Val16Ala）。我们假设这种单核苷酸多态性会影响接受化疗的乳腺癌患者的生存率。
对来自美国（n = 248）和挪威（n = 340）的两个患者群体进行Val16Ala基因分型。采用Kaplan-Meier生存分析和Cox比例风险回归分析来检验Val16Ala与疾病特异性生存之间的关系。
在两个患者群体中，Val16Ala均与乳腺癌预后显著相关。在多变量分析中，丙氨酸等位基因携带者的生存率较低[风险比（HR），美国队列中为2.44，95%置信区间（95%CI）为1.11 - 5.37；挪威队列中，Ala/Ala与Val/Val相比，HR为1.91，95%CI为1.06 - 3.45]。在对合并队列的分析中，这种关联在接受辅助治疗的患者中具有显著性（HR，2.47；95%CI，1.46 - 4.19），但在未接受辅助治疗的患者中不显著（HR，1.47；95%CI，0.57 - 3.74）。在按化疗类型进一步分层后，丙氨酸等位基因的影响主要限于含环磷酰胺的化疗方案（HR，22.0；95%CI，5.22 - 92.9；Ala/Ala与Val/Val相比）。
Val16Ala多态性影响接受含环磷酰胺化疗患者的生存率。这些发现首次为乳腺癌患者环磷酰胺耐药机制提供了证据。
