Different Effects of TERT, TP63, and CYP2A6 Polymorphism on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers
Different Effects of TERT, TP63, and CYP2A6 Polymorphism on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers
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DOI：
10.4236/jct.2011.25093
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发表时间：
2011-12
期刊：
影响因子：
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通讯作者：
M. Shimizu;K. Kiyotani;H. Kunitoh;T. Kamataki;H. Yamazaki
中科院分区：
文献类型：
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作者：
M. Shimizu;K. Kiyotani;H. Kunitoh;T. Kamataki;H. Yamazaki
最近的全基因组关联研究已经确定了肺癌的易感基因，如染色体5p15(端粒酶逆转录酶，TERT和唇腭裂跨膜蛋白1样，CLPTM1L)，15q25(烟碱胆碱能受体α，CHRNA3-CHRNA5)和3q28(肿瘤蛋白p63，TP63)。为了证实最近发现的易感基因(即TERT-CLPTM1L、CHRNA3-CHRNA5和TP63)与1460名日本男性吸烟者(885例肺癌患者和575名健康对照组)之间的关联，进行了重复研究，此前研究表明细胞色素P450 2A6(CYP2A6)受损或缺失多态与肺癌风险的比值比很低。肺癌患者rs2736100在5p15(TERT)的等位基因频率(0.442)显著高于对照组(0.395)，优势比为1.27(95%可信区间为1.07~1.5，P=0.00504)。一系列亚组分析显示rs4488809(tp63，优势比1.21，p=0.0422)和rs2736100(端粒酶逆转录酶，优势比1.47，p=6.40×10-5)与肺腺癌的风险显著相关。在该人群中未发现CHRNA3-CHRNA5与CLPTM1L的显著关联。目前的结果支持复制TERT和TP63基因座与肺腺癌的关联，并提示这些基因座对吸烟者患肺癌风险较高的亚型特异性影响。包括拷贝数多态在内的CYP2A6基因，在大规模的全基因组关联研究中未被研究，可能会影响与大量吸烟相关的肺癌的较低风险。
Recent genome-wide association studies have identified lung cancer susceptibility loci, such as chromosome 5p15 (telomerase reverse transcriptase, TERT and cleft lip and palate transmembrane protein 1-like, CLPTM1L), 15q25 (nicotinic cholinergic receptor α, CHRNA3-CHRNA5), and 3q28 (tumor protein p63, TP63). Replication study was performed to confirm the association of the recently-identified susceptible loci (i.e., TERT-CLPTM1L, CHRNA3-CHRNA5, and TP63) in a total of 1460 male Japanese smokers (885 lung cancer cases and 575 healthy control subjects), which were previously studied for a low odds ratio of impaired or deletion polymorphism in cytochrome P450 2A6 (CYP2A6) for lung cancer risk. The minor allele frequency (0.442) of rs2736100 on 5p15 (TERT) was significantly higher in lung cancer cases than that (0.395) of controls, with an odds ratio of 1.27 (95% CI of 1.07 - 1.50, p = 0.00504). A series of subgroup analyses revealed the significant associations of rs4488809 (TP63, odds ratio of 1.21, p = 0.0422) and rs2736100 (TERT, odds ratio of 1.47, p = 6.40 × 10–5) with the risk of lung adenocarcinoma. No significant association of CHRNA3-CHRNA5 and CLPTM1L was found in this population. The present results support replication of the association of TERT and TP63 loci with lung adenocarcinomas and suggest subtype-specific effects of these loci on higher risk of lung cancer in smokers. The CYP2A6 including copy number polymorphism, uninvestigated in large-scale genome-wide association studies, may influence lower risk to heavy tobacco use-related lung cancer.