Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin, China; Tibet Chengdu branch of West China Hospital, Sichuan University Changdu, China.
Cancer Center, West China Hospital, Sichuan University Chengdu, China.
Thorac Cancer. 2014 May;5(3):232-42. doi: 10.1111/1759-7714.12073. Epub 2014 Apr 22.
The carcinogenic chemicals and reactive oxygen species in tobacco can result in DNA damage. DNA repair genes play an important role in maintaining genome integrity. Genetic polymorphisms of DNA repair genes and smoking may contribute to susceptibility of lung cancer.
In this hospital-based case-control study, we investigated the relationship between 13 tagging single nucleotide polymorphisms (SNPs) in base excision repair pathway and nucleotide excision repair pathway genes, smoking, and lung cancer susceptibility. Thirteen tag SNPs were genotyped in 265 lung cancer patients and 301 healthy controls. Logistic regression and multifactor dimensionality reduction method were applied to explore the association and high-order gene-gene and gene-smoking interaction.
In single tag SNP analysis, XPA rs2808668, XPC rs2733533, and XPD rs1799787 were significantly associated with lung cancer susceptibility. Joint effects analysis of XPA rs2808668, XPC rs2733533 and XPD rs1799787 showed that there was an increased risk of lung cancer with increasing numbers of risk alleles. Haplotype analysis showed that XRCC1 (rs25487, rs1799782, rs3213334) GCC had a positive association with lung cancer. Analysis of gene-gene and gene-smoking interaction by multifactor dimensionality reduction showed that a positive interaction existed between the four genes and smoking. The two-factor model, including XPC rs2755333 and smoking, had the best prediction ability for lung cancer. Compared with the C/C genotype of XPC rs2733533 and no smoking, the combination of genotype A carriers with XPC rs2733533 and heavy smokers (≥30 pack-year) had a 13.32-fold risk of lung cancer.
Our results suggest multiple genetic variants in multiple DNA repair genes may jointly contribute to lung cancer risk through gene-gene and gene-smoking interactions.
烟草中的致癌化学物质和活性氧会导致 DNA 损伤。DNA 修复基因在维持基因组完整性方面发挥着重要作用。DNA 修复基因的遗传多态性和吸烟可能导致肺癌易感性。
本研究采用基于医院的病例对照研究方法，探讨碱基切除修复途径和核苷酸切除修复途径基因中的 13 个标签单核苷酸多态性（SNP）与吸烟和肺癌易感性之间的关系。在 265 例肺癌患者和 301 例健康对照中，对 13 个标签 SNP 进行了基因分型。采用 logistic 回归和多因素降维方法探讨关联和基因-基因及基因-吸烟的交互作用。
在单标签 SNP 分析中，XPA rs2808668、XPC rs2733533 和 XPD rs1799787 与肺癌易感性显著相关。XPA rs2808668、XPC rs2733533 和 XPD rs1799787 的联合效应分析表明，随着风险等位基因数量的增加，肺癌的发病风险增加。单体型分析显示，XRCC1(rs25487、rs1799782、rs3213334) GCC 与肺癌呈正相关。多因素降维分析显示，这些基因与吸烟之间存在正交互作用。XPC rs2755333 和吸烟的两因素模型对肺癌具有最佳的预测能力。与 XPC rs2733533 的 C/C 基因型和不吸烟相比，XPC rs2733533 基因型 A 携带者且重度吸烟者（≥30 包年）患肺癌的风险增加了 13.32 倍。
本研究结果表明，多个 DNA 修复基因中的多个遗传变异可能通过基因-基因和基因-吸烟的相互作用共同导致肺癌的发生风险。
