Hung Rayjean J, Hall Janet, Brennan Paul, Boffetta Paolo
Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
Am J Epidemiol. 2005 Nov 15;162(10):925-42. doi: 10.1093/aje/kwi318. Epub 2005 Oct 12.
Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to cancer risk. However, epidemiologic findings have been inconsistent. The authors conducted meta-analyses of associations between genes in the base excision repair pathway and cancer risk, focusing on three key genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1), and x-ray repair cross-complementing group 1 (XRCC1). They found increased lung cancer risk among subjects carrying the OGG1 Cys/Cys genotype (odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.01, 1.53), using 3,253 cases and 3,371 controls from seven studies; this is consistent with experimental evidence that this isoform exhibits decreased activity. They found a protective effect of the XRCC1 194Trp allele for tobacco-related cancers (OR = 0.86, 95% CI: 0.77, 0.95), using 4,895 cases and 5,977 controls from 16 studies; this is compatible with evidence of lower mutagen sensitivity for this allele. The XRCC1 399Gln/399Gln genotype was associated with increased risk of tobacco-related cancers among light smokers (OR = 1.38, 95% CI: 0.99, 1.94) but decreased risk among heavy smokers (OR = 0.71, 95% CI: 0.51, 0.99), suggesting effect modification by tobacco smoking. There was no association between cancer risk and the APE1/APEX1 Asp148Glu and XRCC1 Arg280His polymorphisms. Recommendations for future studies include pooling of individual data to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental exposure.
DNA修复基因的遗传变异被认为可调节DNA修复能力，并被认为与癌症风险相关。然而，流行病学研究结果并不一致。作者对碱基切除修复途径中的基因与癌症风险之间的关联进行了荟萃分析，重点关注三个关键基因：8-氧鸟嘌呤DNA糖基化酶（OGG1）、脱嘌呤/脱嘧啶内切酶（APE1/APEX1）和X射线修复交叉互补基因1（XRCC1）。他们发现，在七项研究中的3253例病例和3371例对照中，携带OGG1 Cys/Cys基因型的受试者患肺癌的风险增加（优势比（OR）=1.24，95%置信区间（CI）：1.01，1.53）；这与该异构体活性降低的实验证据一致。他们发现，在16项研究中的4895例病例和5977例对照中，XRCC1 194Trp等位基因对烟草相关癌症具有保护作用（OR = 0.86，95% CI：0.77，0.95）；这与该等位基因突变敏感性较低的证据相符。XRCC1 399Gln/399Gln基因型与轻度吸烟者患烟草相关癌症的风险增加相关（OR = 1.38，95% CI：0.99，1.94），但与重度吸烟者患癌风险降低相关（OR = 0.71，95% CI：0.51，0.99），表明吸烟存在效应修饰作用。癌症风险与APE1/APEX1 Asp148Glu多态性和XRCC1 Arg280His多态性之间无关联。对未来研究的建议包括汇总个体数据以促进对多基因效应的评估，以及详细分析环境暴露的效应修饰作用。
