Functional FEN1 polymorphisms are associated with DNA damage levels and lung cancer risk

Authors

  • Ming Yang,

    1. 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
    2. Beijing Key Laboratory for Cancer Prevention, Beijing, People's Republic of China
    Search for more papers by this author
    • Ming Yang and Huan Guo contributed equally to this work.

  • Huan Guo,

    1. Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for more papers by this author
    • Communicated by Michael Dean

  • Chen Wu,

    1. 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
    2. Beijing Key Laboratory for Cancer Prevention, Beijing, People's Republic of China
    Search for more papers by this author
  • Yuefeng He,

    1. Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for more papers by this author
  • Dianke Yu,

    1. 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
    2. Beijing Key Laboratory for Cancer Prevention, Beijing, People's Republic of China
    Search for more papers by this author
  • Li Zhou,

    1. Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for more papers by this author
  • Fang Wang,

    1. Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for more papers by this author
  • Jian Xu,

    1. 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
    Search for more papers by this author
  • Wen Tan,

    1. 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
    2. Beijing Key Laboratory for Cancer Prevention, Beijing, People's Republic of China
    Search for more papers by this author
  • Guanghai Wang,

    1. 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
    2. Beijing Key Laboratory for Cancer Prevention, Beijing, People's Republic of China
    Search for more papers by this author
  • Binghui Shen,

    1. Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California
    Search for more papers by this author
  • Jing Yuan,

    1. Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    Search for more papers by this author
  • Tangchun Wu,

    Corresponding author
    1. Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    • School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
    Search for more papers by this author
  • Dongxin Lin

    Corresponding author
    1. 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
    2. Beijing Key Laboratory for Cancer Prevention, Beijing, People's Republic of China
    • Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
    Search for more papers by this author

Abstract

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. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.

Ancillary