Smoking-related Genomic Signatures in Non-Small Cell Lung Cancer
Smoking-related Genomic Signatures in Non-Small Cell Lung Cancer
复制标题
DOI：
10.1164/rccm.200801-142oc
复制
发表时间：
2008-12-01
影响因子：
24.7
通讯作者：
Spitz, Margaret R.
中科院分区：
文献类型：
--
作者：
Massion, Pierre P.;Zou, Yong;Spitz, Margaret R.
基本原理：吸烟占所有肺癌的85%。为了进一步了解肺癌的分子发病机制，我们确定了吸烟史是否会导致非小细胞肺癌(NSCLC)中出现特异的基因组改变。目的：确定非小细胞肺癌中与吸烟史或DNA修复能力相关的基因拷贝数变化。方法：本研究选择75例NSCLC患者，来自目前、无吸烟史或既往吸烟史的患者，包括包年信息。组织切片经显微切割、DNA提取、纯化、随机引物法标记后与细菌人工染色体(BAC)芯片杂交。归一化比率与吸烟史相关，并通过体外淋巴细胞检测同一患者的DNA修复能力。测量和主要结果：我们在NSCLC中识别出与吸烟相关的基因组特征，总体准确率为74%。来自当前吸烟者的肺癌拷贝数改变的数量最多。与吸烟最显著相关的基因组区域位于60个区域内，在功能上与控制细胞周期M期、染色体分离和DNA甲基化的基因相关。数据的核实是通过公共领域的数据和实时定量聚合酶链式反应提供的。基因组异常与DNA修复能力之间的相关性未达到统计学意义。结论：这些发现表明吸烟史在肺癌的DNA中留下了特定的基因组特征，提示这些变化可能反映了癌症发生的新的分子途径。
Rationale: Tobacco smoking is responsible for 85% of all lung cancers. To further our understanding of the molecular pathogenesis of lung cancer, we determined whether smoking history leads to the emergence of specific genomic alterations found in non-small cell lung cancer (NSCLC).Objectives: To identify gene copy number alterations in NSCLCs associated with smoking history or DNA repair capacity.Methods: Seventy-five NSCLCs were selected for this study from patients with current, none, or past smoking history, including pack year information. Tissue sections were microdissected, and DNA was extracted, purified, and labeled by random priming before hybridization onto bacterial artificial chromosome (BAC) arrays. Normalized ratios were correlated with smoking history and DNA repair capacity was measured by an in vitro lymphocyte assay in the same patients.Measurements and Main Results: We identified smoking-related genomic signatures in NSCLCs that could be predicted with an overall 74% accuracy. Lung tumors arising from current-smokers had the greatest number of copy number alterations. The genomic regions most significantly associated with smoking were located within 60 regions and were functionally associated with genes controlling the M phase of the cell cycle, the segregation of chromosomes, and the methylation of DNA. Verification of the data is provided from data in the public domain and by quantitative real-time polymerase chain reaction. The associations between genomic abnormalities and DNA repair capacity did not reach statistical significance.Conclusions: These findings indicate that smoking history leaves a specific genomic signature in the DNA of lung tumors and suggest that these alterations may reflect new molecular pathways to cancer development.