Guest Editorial
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Guest Editorial Epidemiological studies carried out as early as the 1950s established an association between smoking and lung cancer that literally jumped out at us: smokers accounted for 70–80 per cent of lung cancer patients.1 More recent epidemiological studies have reliably replicated this finding.2 All of the epidemiological studies, both old and new, also found that a minority (10–15 per cent) of smokers contract this often fatal disease. Consequently, the medical and scientific communities have been infatuated with the question: why do a minority of smokers develop lung cancer? Clearly, this is an important question, given that lung cancer accounted for approximately 30 per cent (160,390) of all cancer-related deaths reported in the USA in 2007.3 The famous statistician, Sir Ronald Fisher, was the first to suggest that genes regulate susceptibility to smoking-associated lung cancer in a 1958 study that determined concordance rates for lung cancer and smoking in monozygotic (MZ) and dizygotic (DZ) twins.4 Fisher concluded that genetic factors do not influence lung cancer because the MZ and DZ concordances for lung cancer are the same. This conclusion has been ignored, in part, because more recent twins studies that included larger sample sizes have detected significantly higher concordance for lung cancer in MZ twins versus DZ twins5,6 and because lung cancer shows familial aggregation.7,8 The generally held opinion seems to be that only some smokers contract lung cancer because genes, probably more than one, play vital roles in regulating susceptibility to developing lung cancer. While the generally held opinion may be correct, it is clear from those studies that have attempted to quantify it that genetic influence on lung cancer is moderate to low. For example, 8 per cent heritability for lung cancer was calculated from the 9.6 million subject Swedish Family-Cancer database,9 and heritability estimates
derived from twins and family studies are in the 10 per cent range.10,11
Candidate gene and genome-wide association studies of lung cancer Identifying genes that play a causal role in the development of lung cancer has been a major source of entertainment and frustration for geneticists for the past 50 years. Studies that evaluate candidate genes have been especially popular because they are often based on what appears to be sound biology. If the basic science branch of cancer research identifies a gene product that seems to influence the cancer process, geneticists have frequently attempted to identify polymorphisms in the human genes and have then designed studies to determine whether these polymorphisms influence susceptibility to lung cancer. Hundreds, if not thousands, of studies have attempted to determine whether a long list of candidate genes might influence the development of lung cancer. In a 2008 review of the literature, Risch and Plass conclude that lung cancer is a complex disease, influenced by low-penetrance polymorphisms in multiple genes, and that epigenetic factors may also be important.1
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