Genetic basis for susceptibility to lung cancer: Recent progress and future directions

Lung cancer is the leading cause of cancer death worldwide, and cigarette smoking is the major environmental factor for its development. To elucidate the genetic differences in the susceptibility to lung cancer among individuals, genetic factors involved in tobacco-induced lung cancers have been extensively investigated and a number of genetic polymorphisms have been identified to date as candidates. Most of the polymorphisms identified are of genes encoding proteins associated with the activity to metabolize tobacco smoke carcinogens and to suppress mutations induced by those carcinogens, and functional significances have been elucidated for some of these polymorphisms. However, the significance of these polymorphisms in the contribution to lung cancer development still remains unclear. Recently, several novel lung cancer susceptibility genes, including those on chromosomes 5p15.33, 6p21, and 15q24-25.1, have been identified by large-scale genome-wide association (GWA) studies. The 15q25 region contains three nicotine acetylcholine receptor subunit genes, and their polymorphisms have been also reported as being associated with nicotine dependence. The 5p15.33 region is associated with risks specifically for lung adenocarcinoma, the commonest histological type and weakly associated with smoking. This locus has been shown to be associated with risks for a wide variety of cancers, including lung adenocarcinoma. Associations of the 6q21 region have not been consistently replicated among studies. The 6q23-25 and 13q31.3 regions were also identified by recent GWA studies as being associated with risk for lung cancer, particularly in never-smokers. However, contributions of genetic differences on these five loci to the susceptibility to overall lung cancer seem to be small. There are several molecular pathways for the development of lung adenocarcinomas, and environmental factors for their development are still unclear, especially those in never-smokers. In addition, geographic differences as well as gender differences in lung cancer risk have been indicated. Furthermore, various genes identified by candidate gene association studies have not been reevaluated for their significance together with genes identified by GWA studies in the same population. Therefore, further studies will be necessary to assess the individual susceptibility to lung cancer based on the combination of polymorphisms in multiple genes, and to establish a novel way of evaluating the individual risk for lung cancer for its prevention.