Udler Miriam, Maia Ana-Teresa, Cebrian Arancha, Brown Clement, Greenberg David, Shah Mitul, Caldas Carlos, Dunning Alison, Easton Douglas, Ponder Bruce, Pharoah Paul
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
J Clin Oncol. 2007 Jul 20;25(21):3015-23. doi: 10.1200/JCO.2006.10.0099.
The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer.
We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer.
Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes.
These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.
乳腺癌患者的预后在个体间差异很大，遗传因素可能有助于解释这种差异。特别令人感兴趣的是参与抵御活性氧（ROS）的基因，因为ROS被认为会导致DNA损伤并促进癌症的发病机制。
我们研究了54个多态性位点与4470例乳腺癌女性患者生存情况之间的关联，这些多态性位点标记了参与氧化损伤修复的10个基因（CAT、SOD1、SOD2、GPX1、GPX4、GSR、TXN、TXN2、TXNRD1和TXNRD2）中的已知常见变异（次要等位基因频率>0.05）。
即使在进行多重假设检验校正后，GPX4基因中的两个单核苷酸多态性（SNP）（rs713041和rs757229）仍与全因死亡率相关（校正后P = 0.0041和P = 0.0035）。这些SNP相互关联（r2 = 0.61）。GPX4 rs713041位于GPX4 3'非翻译区的硒代半胱氨酸插入序列元件附近，该SNP的罕见等位基因与死亡风险增加相关，每个携带的罕见等位基因的风险比为1.27（95%CI，1.13至1.43）。在调整肿瘤分期、分级或雌激素受体状态后，这种效应并未减弱。我们发现，与罕见等位基因相比，常见等位基因在正常淋巴细胞、正常乳腺和乳腺肿瘤中优先表达，但不同基因型的GPX4 mRNA总水平没有差异。
这些数据为GPX4基因的常见变异与乳腺癌诊断后的预后相关这一假说提供了有力支持。
