Cebrian Arancha, Pharoah Paul D, Ahmed Shahana, Smith Paula L, Luccarini Craig, Luben Robert, Redman Karen, Munday Hannah, Easton Douglas F, Dunning Alison M, Ponder Bruce A J
Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge,Worts Causeway, Cambridge CB1 8RN, UK.
Cancer Res. 2006 Jan 15;66(2):1225-33. doi: 10.1158/0008-5472.CAN-05-1857.
It is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damage leading to genetic alterations and provoking uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Reactive oxygen species have been related to the etiology of cancer as they are known to be mitogenic and therefore capable of tumor promotion. The aim of this study was to assess the role of common variation in 10 polymorphic genes coding for antioxidant defense enzymes in modulating individual susceptibility to breast cancer using a case-control study (N cases = 4,474 and N controls = 4,580). Both cases and controls were from the East Anglian region of the United Kingdom. We have identified a set of 54 single nucleotide polymorphisms (SNPs) that efficiently tag all the known SNPs in the 10 genes and are also expected to tag any unknown SNPs in each gene. We found no evidence for association of common variants in SOD1, SOD2, GPX1, GPX4, GSR, TXNRD1, and TXN2. There was borderline evidence for association of variants in CAT g27168a {P [2 degrees of freedom (df)] = 0.05}, TXN t2715c [P (2 df) = 0.007], and TXNRD2 A66S and TXNRD2 g23524a (P(trend) = 0.074 and 0.046, respectively). For TXNRD2 A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles. Even if confirmed, these four alleles would account for just 0.32% of the excess familial risk of breast cancer.
一般认为，乳腺癌的发生是累积性基因损伤的结果，这种损伤会导致基因改变，引发细胞不受控制地增殖和/或异常程序性细胞死亡，即细胞凋亡。活性氧与癌症病因有关，因为它们已知具有促有丝分裂作用，因此能够促进肿瘤生长。本研究的目的是通过病例对照研究（病例数 = 4474，对照数 = 4580）评估编码抗氧化防御酶的10个多态性基因中的常见变异在调节个体对乳腺癌易感性方面的作用。病例和对照均来自英国东安格利亚地区。我们确定了一组54个单核苷酸多态性（SNP），它们能有效标记这10个基因中所有已知的SNP，并且预计也能标记每个基因中任何未知的SNP。我们没有发现超氧化物歧化酶1（SOD1）、超氧化物歧化酶2（SOD2）、谷胱甘肽过氧化物酶1（GPX1）、谷胱甘肽过氧化物酶4（GPX4）、谷胱甘肽还原酶（GSR）、硫氧还蛋白还原酶1（TXNRD1）和硫氧还蛋白2（TXN2）中常见变异存在关联的证据。过氧化氢酶（CAT）g27168a [自由度（df）为2时的P值 = 0.05]、硫氧还蛋白（TXN）t2715c [自由度为2时的P值 = 0.007]以及硫氧还蛋白还原酶2（TXNRD2）A66S和TXNRD2 g23524a [趋势P值分别为0.074和0.046]存在边缘关联证据。对于TXNRD2 A66S [AS与AA相比：比值比（OR）为1.05；95%置信区间（95%CI）为0.96 - 1.15；SS与AA相比：OR为1.12；95%CI为0.98 - 1.29]，有生物信息学数据表明它具有功能，但在被视为明确的乳腺癌易感等位基因之前，需要在独立数据集中进行验证。即使得到验证，这四个等位基因也仅占乳腺癌家族性额外风险的0.32%。
