Genetic Susceptibility to Lung Cancer

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Lung cancer is the most common cause of cancer death in the world. Environmental factors, particularly cigarette smoking, are of paramount importance in determining lung cancer risk. Lung cancer and chronic obstructive lung disease are likely to share some common susceptibility genes, but these have not yet been identified. Evidence from various sources, including twin studies, segregation analyses, and case-control studies, support a heritable component to lung cancer risk in humans. As with many common diseases, susceptibility genes for lung cancer appear to be of low penetrance. Family studies of lung cancer susceptibility using linkage analysis and positional cloning have not been reported; however, a consortium is currently carrying out such studies, and results may soon be available. Association studies support lung cancer risk being partly determined by genes that control the metabolism of carcinogens found in tobacco smoke, with the heritable effects being most prominent in smokers with shorter smoking histories. Of these, the CYP1A1 and GSTM1 polymorphisms have been most consistently implicated. In the mouse, an oligonucleotide repeat polymorphism within an intron of the Ki-ras oncogene is the major lung cancer susceptibility locus; however this locus is not clearly involved in susceptibility to lung cancer in the human. Further understanding of the genetic basis of lung cancer susceptibility has many important implications, ranging from targeting prevention and screening efforts to the most highly susceptible population to developing novel chemopreventive therapies.

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