Sakoda Lori C, Loomis Melissa M, Doherty Jennifer A, Julianto Liberto, Barnett Matt J, Neuhouser Marian L, Thornquist Mark D, Weiss Noel S, Goodman Gary E, Chen Chu
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Int J Mol Epidemiol Genet. 2012;3(1):1-17. Epub 2012 Feb 5.
Since nucleotide excision repair (NER) is primarily responsible for detecting and removing bulky DNA lesions induced by tobacco smoke in the respiratory tract, single nucleotide polymorphisms (SNPs) in NER protein-encoding genes may influence lung cancer risk, particularly in smokers. Studies testing this hypothesis have produced inconsistent results, with most analyzing a few SNPs in relatively small population samples. In a study nested in the Beta- Carotene and Retinol Efficacy Trial, we examined 79 tag and previously reported risk-associated SNPs in the ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, POLE, XPA, and XPC genes in 744 lung cancer cases and 1,477 controls, all of whom were non-Hispanic white smokers. Using logistic regression, odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to estimate lung cancer risk associated with SNP genotypes and haplotypes, adjusting for case-control matching factors. Lung cancer risk was modestly associated with LIG1 rs156640 (OR per G allele, 1.23; 95% CI, 1.08-1.40), rs156641 (OR per A allele, 1.23; 95% CI, 1.08-1.40), and rs8100261 (OR per A allele, 0.83; 95% CI, 0.76-0.98); XPA rs3176658 (OR per A allele, 0.83; 95% CI, 0.69-1.00); and ERCC2 rs50871 (OR per C allele, 1.15; 95% CI: 1.01-1.30). Associations with LIG1 and XPA, but not ERCC2, haplotypes were found. The results of this study and others suggest that inherited variants in LIG1 and possibly other NER genes may predispose to smoking-related lung cancer. Given that chance likely accounts for one or more of the associations observed, replication of our findings is needed.
由于核苷酸切除修复（NER）主要负责检测和清除呼吸道中由烟草烟雾诱导产生的大块DNA损伤，NER蛋白编码基因中的单核苷酸多态性（SNP）可能会影响肺癌风险，尤其是在吸烟者中。检验这一假设的研究结果并不一致，大多数研究在相对较小的人群样本中分析了少数几个SNP。在一项嵌套于β-胡萝卜素和视黄醇功效试验的研究中，我们检测了744例肺癌病例和1477例对照中ERCC1、ERCC2、ERCC3、ERCC4、ERCC5、LIG1、POLE、XPA和XPC基因中的79个标签SNP以及先前报道的与风险相关的SNP，所有这些研究对象均为非西班牙裔白人吸烟者。采用逻辑回归分析，计算比值比（OR）和95%置信区间（95%CI），以评估与SNP基因型和单倍型相关的肺癌风险，并对病例对照匹配因素进行校正。肺癌风险与LIG1基因的rs156640（每G等位基因的OR为1.23；95%CI为1.08 - 1.40）、rs156641（每A等位基因的OR为1.23；95%CI为1.08 - 1.40）和rs8100261（每A等位基因的OR为0.83；95%CI为0.76 - 0.98）；XPA基因的rs3176658（每A等位基因的OR为0.83；95%CI为0.69 - 1.00）；以及ERCC2基因的rs50871（每C等位基因的OR为1.15；95%CI：1.01 - 1.30）存在适度关联。还发现了与LIG1和XPA基因单倍型的关联，但未发现与ERCC2基因单倍型的关联。本研究及其他研究结果表明，LIG1基因以及可能其他NER基因中的遗传变异可能使个体易患吸烟相关肺癌。鉴于观察到的关联可能存在偶然因素，因此需要对我们的研究结果进行重复验证。
