Effect modification by smoking on the association between genetic polymorphisms in oxidative stress genes and colorectal cancer risk.

There is growing evidence that oxidative stress induced by reactive oxygen species (ROS) is involved in colorectal carcinogenesis by affecting cellular processes critical in tumor development (1). Crucial genes in the oxidative stress pathway include catalase (CAT), manganese superoxide dismutase (MnSOD), myeloperoxidase (MPO), and endothelial nitric oxide synthase (eNOS), coding for enzymes that are related to oxidative stress mechanisms by either neutralizing or generating ROS. Genetic polymorphisms in oxidative stress genes could alter colorectal cancer risk, and this association could be modified by increased ROS exposure following smoking. Tobacco smoke contains highly reactive free radicals and has been associated with colorectal cancer risk in a dose-dependent fashion. In accordance with the biological hypothesis that smoking may act as an initiator of colorectal tumorigenesis and, thus, requires a long induction period (2, 3), we found that long duration of smoking at a high cumulative dose increases colorectal cancer risk (4). In the present study, we assessed potential effect modification by long-term and high-dose smoking on the association between functional genetic polymorphisms in oxidative stress genes [CAT CT (rs1001179), MnSOD ValAla (rs4880), MPO GA (rs2333227), and eNOS GluAsp (rs1799983)] and colorectal cancer risk in a German case-control study.