肿瘤坏死因子-α基因多态性与非小细胞肺癌易感性及严重程度的关联

Association of TNF-alpha polymorphism with susceptibility to and severity of non-small cell lung cancer.

作者信息

Shih Chuen-Ming, Lee Yao-Ling, Chiou Hui-Ling, Chen Wei, Chang Gee-Chen, Chou Ming-Chih, Lin Long-Yau

机构信息

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan.

出版信息

Lung Cancer. 2006 Apr;52(1):15-20. doi: 10.1016/j.lungcan.2005.11.011. Epub 2006 Feb 14.

DOI:10.1016/j.lungcan.2005.11.011

PMID:16476505

Abstract

BACKGROUND

Genetic polymorphisms in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene are involved in the regulation of expression levels and have been associated with various inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter region of the TNF-alpha gene (-308 G/A and -238 G/A) for their role in the susceptibility to and severity of non-small cell lung cancer (NSCLC), by means of an allelic association study.

METHODS

Using a case-control study design, lung cancer patients (n = 202) and appropriate age- and sex-matched controls recruited from the health check-up unit (n = 205) were subjected to genotype analysis for these polymorphisms, using a high-throughput allelic discrimination method.

RESULTS

Genotype was analyzed using the polymerase chain reaction-restriction fragment length polymorphism technique with genomic DNA isolated from peripheral blood lymphocytes. Overall, the distribution of the genotype frequencies of TNF-alpha-308 A/G and -238 A/G were significantly different between the lung cancer patients and the healthy controls, and also different between patients with lung cancers of various stages (p < 0.0001). Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen for individuals with TNF-alpha-308 AA/GA genotypes against GG genotype (an OR of 3.75, 95% CI 2.38-5.92, p < 0.0001), and lower ORs were seen for individuals with TNF-alpha-238 AA/GA genotypes against GG genotype (an OR of 0.26, 95% CI 0.13-0.50, p < 0.0001). The patients carrying a homologous AA or heterologous GA genotype at TNF-308 (p = 0.017), or a homologous GG genotype at TNF-238 (p = 0.001), had a tendency to advanced disease.

CONCLUSIONS

A significant association between the 308 G/A and 238 G/A polymorphisms in the promoter region of TNF-alpha and the susceptibility to lung cancer was demonstrated. Also, these two polymorphisms were associated with the severity of lung cancer. The -308 A allele has a promotive effect for lung cancer development and progression, whereas the -238 A allele has a protective function against lung cancers.

摘要

背景

肿瘤坏死因子-α（TNF-α）基因启动子区域的基因多态性参与表达水平的调控，并与多种炎症和恶性疾病相关。我们通过等位基因关联研究，调查了TNF-α基因启动子区域的两种多态性（-308 G/A和-238 G/A）在非小细胞肺癌（NSCLC）易感性和严重程度中的作用。

方法

采用病例对照研究设计，对从健康体检单位招募的肺癌患者（n = 202）和年龄及性别匹配的合适对照（n = 205），使用高通量等位基因鉴别方法对这些多态性进行基因分型分析。

结果

使用聚合酶链反应-限制性片段长度多态性技术，对外周血淋巴细胞分离的基因组DNA进行基因型分析。总体而言，肺癌患者与健康对照之间，TNF-α -308 A/G和-238 A/G基因型频率的分布存在显著差异，不同分期肺癌患者之间也存在差异（p < 0.0001）。逻辑回归分析显示，TNF-α -308 AA/GA基因型个体相对于GG基因型个体患肺癌的比值比（OR）更高（OR为3.75，95% CI 2.38 - 5.92，p < 0.0001），而TNF-α -238 AA/GA基因型个体相对于GG基因型个体的OR更低（OR为0.26，95% CI 0.13 - 0.50，p < 0.0001）。携带TNF-308同源AA或异源GA基因型（p = 0.017），或TNF-238同源GG基因型（p = 0.001）的患者有疾病进展的倾向。