Zhang Yan, Breitling Lutz P, Balavarca Yesilda, Holleczek Bernd, Schöttker Ben, Brenner Hermann
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany.
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg, D-69120, Germany.
Int J Cancer. 2016 Dec 1;139(11):2482-92. doi: 10.1002/ijc.30374. Epub 2016 Aug 22.
Epigenome-wide association studies have established methylation patterns related to smoking, the major risk factor of lung cancer (LC), which are distinct from methylation profiles disclosed in LC patients. This study simultaneously investigated associations of smoking-associated and LC-related methylation markers with LC mortality. DNA methylation was determined by HM450K assay in baseline blood samples of 1,565 older adults in a population-based case-cohort study. The associations of 151 smoking-associated CpGs (smoCpGs) and 3,806 LC-related CpGs (caCpGs) with LC mortality were assessed by weighted Cox regression models, controlling for potential confounders. Multi-loci methylation scores were separately constructed based on smoCpGs and caCpGs. During a median follow-up of 13.8 years, 60 participants who had a first diagnosis of LC died from LC. The average time between sample collection and LC diagnosis was 5.8 years. Hypomethylation at 77 smoCpGs and 121 caCpGs, and hypermethylation at 4 smoCpGs and 66 caCpGs were associated with LC mortality. The associations were much stronger for smoCpGs than for caCpGs. Hazard ratios (95% CI) were 7.82 (2.91-21.00) and 2.27 (0.75-6.85), respectively, for participants in highest quartile of Score I (based on 81 smoCpGs) and Score II (based on 187 caCpGs), compared with participants in the corresponding lower three quartiles. Score I outperformed Score II, with an optimism-corrected C-index of 0.87 vs. 0.77. In conclusion, although methylation changes of both smoking-associated and LC-related genes are associated with LC mortality, only smoking-associated methylation markers predict LC mortality with high accuracy, and may thus serve as promising candidates to identify high risk populations for LC screening.
全基因组关联研究已经确定了与吸烟相关的甲基化模式，吸烟是肺癌（LC）的主要危险因素，这些模式与肺癌患者中发现的甲基化谱不同。本研究同时调查了与吸烟相关和与肺癌相关的甲基化标志物与肺癌死亡率的关联。在一项基于人群的病例队列研究中，通过HM450K检测法测定了1565名老年人基线血样中的DNA甲基化。通过加权Cox回归模型评估了151个与吸烟相关的CpG（smoCpG）和3806个与肺癌相关的CpG（caCpG）与肺癌死亡率的关联，并控制了潜在的混杂因素。分别基于smoCpG和caCpG构建了多位点甲基化评分。在中位随访13.8年期间，60名首次诊断为肺癌的参与者死于肺癌。样本采集与肺癌诊断之间的平均时间为5.8年。77个smoCpG和121个caCpG的低甲基化，以及4个smoCpG和66个caCpG的高甲基化与肺癌死亡率相关。smoCpG的关联比caCpG更强。与相应较低三分位数的参与者相比，得分I（基于81个smoCpG）和得分II（基于187个caCpG）最高四分位数的参与者的风险比（95%CI）分别为7.82（2.91-21.00）和2.27（0.75-6.85）。得分I优于得分II，乐观校正的C指数分别为0.87和vs0.77。总之，尽管与吸烟相关和与肺癌相关基因的甲基化变化均与肺癌死亡率相关，但只有与吸烟相关的甲基化标志物能高精度地预测肺癌死亡率，因此可能是识别肺癌筛查高危人群的有前景的候选标志物。
