Yang Ming, Guo Huan, Wu Chen, He Yuefeng, Yu Dianke, Zhou Li, Wang Fang, Xu Jian, Tan Wen, Wang Guanghai, Shen Binghui, Yuan Jing, Wu Tangchun, Lin Dongxin
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Hum Mutat. 2009 Sep;30(9):1320-8. doi: 10.1002/humu.21060.
Flap endonuclease 1 (FEN1) is a key enzyme in maintaining genomic stability and protecting against carcinogenesis. This study investigated whether functional variations in FEN1 gene are associated with DNA damage and lung cancer risk. Thirty DNA samples were sequenced to identify variants and function of the variants was examined by a set of biochemical assays. DNA damage levels were detected by comet assays in a cohort of 303 coke-oven workers and 297 controls. The association with lung cancer risk was examined in two independent case-control panels consisted of a total 1,840 lung cancer patients and 1,958 controls. We identified two single nucleotide polymorphisms (SNPs) located in the FEN1 promoter c.-69G>A (rs174538:G>A) and 3'-untranslational region c.4150G>T (rs4246215:G>T) that were associated with reduced FEN1 expression. Among coke-oven workers, DNA damage levels were significantly higher in the -69GG or GA carriers compared with the -69AA carriers. The -69GG or 4150GG carriers had a significantly increased risk for developing lung cancer compared with the -69AA or 4150TT carriers. These results highlight FEN1 as an important gene in human carcinogenesis and genetic polymorphisms in FEN1 confer susceptibility to lung cancer.
瓣内切核酸酶1（FEN1）是维持基因组稳定性和预防癌症发生的关键酶。本研究调查了FEN1基因的功能变异是否与DNA损伤和肺癌风险相关。对30个DNA样本进行测序以鉴定变异，并通过一系列生化分析检测变异的功能。在303名焦炉工人和297名对照组成的队列中，通过彗星试验检测DNA损伤水平。在两个独立的病例对照小组中检查与肺癌风险的关联，这两个小组共包括1840名肺癌患者和1958名对照。我们鉴定出位于FEN1启动子区c.-69G>A（rs174538:G>A）和3'-非翻译区c.4150G>T（rs4246215:G>T）的两个单核苷酸多态性（SNP），它们与FEN1表达降低相关。在焦炉工人中，-69GG或GA携带者的DNA损伤水平显著高于-69AA携带者。与-69AA或4150TT携带者相比，-69GG或4150GG携带者患肺癌的风险显著增加。这些结果突出了FEN1作为人类致癌作用中的一个重要基因，且FEN1中的基因多态性赋予了对肺癌的易感性。
