Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Int J Radiat Oncol Biol Phys. 2015 Aug 1;92(5):1084-1092. doi: 10.1016/j.ijrobp.2015.04.011. Epub 2015 Apr 11.
To identify single-nucleotide polymorphisms (SNPs) in oxidative stress-related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy.
Using a 2-stage design, 305 SNPs in 59 candidate genes were investigated in the discovery phase in 753 breast cancer patients from 2 prospective cohorts from Germany. The 10 most promising SNPs in 4 genes were evaluated in the replication phase in up to 1883 breast cancer patients from 6 cohorts identified through the Radiogenomics Consortium. Outcomes of interest were late skin toxicity and fibrosis of the breast, as well as an overall toxicity score (Standardized Total Average Toxicity). Multivariable logistic and linear regression models were used to assess associations between SNPs and late toxicity. A meta-analysis approach was used to summarize evidence.
The association of a genetic variant in the base excision repair gene XRCC1, rs2682585, with normal tissue late radiation toxicity was replicated in all tested studies. In the combined analysis of discovery and replication cohorts, carrying the rare allele was associated with a significantly lower risk of skin toxicities (multivariate odds ratio 0.77, 95% confidence interval 0.61-0.96, P=.02) and a decrease in Standardized Total Average Toxicity scores (-0.08, 95% confidence interval -0.15 to -0.02, P=.016).
Using a stage design with replication, we identified a variant allele in the base excision repair gene XRCC1 that could be used in combination with additional variants for developing a test to predict late toxicities after radiation therapy in breast cancer patients.
鉴定与接受放射治疗的乳腺癌患者发生晚期毒性相关的氧化应激相关基因中的单核苷酸多态性（SNP）。
使用两阶段设计，在来自德国的 2 个前瞻性队列的 753 例乳腺癌患者中，在发现阶段研究了 59 个候选基因中的 305 个 SNP。在通过放射基因组学联盟确定的 6 个队列中，对 4 个基因中 10 个最有前途的 SNP 进行了多达 1883 例乳腺癌患者的复制阶段评估。感兴趣的结局是晚期皮肤毒性和乳房纤维化，以及整体毒性评分（标准化总平均毒性）。多变量逻辑回归和线性回归模型用于评估 SNP 与晚期毒性之间的关联。采用荟萃分析方法总结证据。
在碱基切除修复基因 XRCC1 中的遗传变异 rs2682585 与正常组织晚期放射毒性的关联在所有测试研究中均得到了复制。在发现和复制队列的综合分析中，携带罕见等位基因与皮肤毒性的风险显著降低相关（多变量优势比 0.77，95%置信区间 0.61-0.96，P=.02），并且标准化总平均毒性评分降低（-0.08，95%置信区间 -0.15 至 -0.02，P=.016）。
使用具有复制的阶段设计，我们鉴定了碱基切除修复基因 XRCC1 中的一个变异等位基因，该等位基因可与其他变异基因结合，用于开发一种测试方法，以预测乳腺癌患者放射治疗后的晚期毒性。
