Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1360-8. doi: 10.1016/j.ijrobp.2009.07.1675. Epub 2010 Feb 18.
Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP).
A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays.
During the median 22-month follow-up, 44 (17.4%) patients developed grade > or = 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07-5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16-5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines (p < 0.001) and in individual lung tissue samples (p = 0.003), which supported the results of the association study.
Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.
由于共济失调毛细血管扩张突变（ATM）蛋白在双链 DNA 断裂修复、细胞周期检查点控制和放射敏感性中发挥关键作用，我们假设该基因的变异可能与放射性肺炎（RP）有关。
本研究共纳入 253 例 2004 年至 2006 年期间接受胸部放疗的肺癌患者。采用常见不良事件术语标准 3.0 版对 RP 进行分级。采用血液淋巴细胞中的 DNA 对 ATM 基因中的 5 个单核苷酸多态性（SNP）进行基因分型。采用 Cox 模型计算 RP 基因型的危险比（HR）和 95%置信区间（CI），并调整临床因素。通过生化测定研究与 RP 相关的 ATM SNP 的功能。
在中位 22 个月的随访期间，44 例（17.4%）患者发生了 > = 2 级 RP。在多变量 Cox 回归模型中，调整其他临床预测因素后，我们发现两个 ATM 变体与增加 RP 风险独立相关。它们是 111G > A 多态性（HR，2.49；95%CI，1.07-5.80）和 ATM 126713G > A 多态性（HR，2.47；95%CI，1.16-5.28）。此外，在细胞系中（p < 0.001）和个体肺组织样本中（p = 0.003）均显示出 ATM 表达的基因型依赖性差异，这支持了关联研究的结果。
ATM 的遗传多态性与 RP 风险显著相关。这些变体可能通过调节 ATM 表达来发挥作用，并可作为预测胸部放疗患者 RP 的独立生物标志物。
