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 [12].
Three recently published studies used the genome-wide association study (GWAS) approach to identify genes that contribute to lung cancer [13–15]. All three studies used large panels of single nucleotide polymorphisms (SNPs) and large subject pools, affording sample sizes that should have provided adequate power to detect a genetic influence that contributes to as little as 2-3 per cent of the variance. It is somewhat surprising that a GWAS identified anything, given that the heritability for lung cancer seems to be so very low (<10 per cent), but all of these studies detected significant associations between lung cancer and the same cluster of genes resident on chromosome 15. This gene cluster encodes three neuronal nicotinic cholinergic receptor (nAChR) subunit genes: α3 (CHRNA3), α5 (CHRNA5) and β4 (CHRNB4). The strongest association with lung cancer was found with CHRNA5. The fact that three different studies, using large sample sizes, yielded identical results must be viewed as provocative, if not downright exciting.
The GWAS approach might be described as a wide-eyed innocence approach, in that it is not burdened by preconceptions; all genes are fair game. This strength can also be a weakness, because once a gene has been discovered, researchers must suggest a mechanism that might explain how a polymorphism associated with the gene contributes to variation in a phenotype of interest. Providing a mechanism often involves obtaining answers to questions, such as: (1) Is the gene product expressed in the right place (e.g. is a lung cancer gene expressed in the lung)? (2) Does the polymorphism affect expression level or function? Obviously, it is not absolutely necessary for a lung cancer gene to be expressed in the lung, or that a polymorphism affects expression level or function, but it certainly would be convenient. Excitement concerning the nAChR gene cluster finding is enhanced by the observations that α5 mRNA and protein are expressed in lung epithelial cells, and by the demonstration that one of the CHRNA5 polymorphisms results in an aspartic acid-asparagine switch at position 398 (second cytoplasmic loop of the α5 nAChR subunit gene product) that affects receptor function when expressed as α4α5β2 nAChRs in HEK cells [16]. We seem to have nearly everything: replication of the finding in three large studies and demonstration that the gene product is found in the lung and that one of strongest association polymorphisms alters receptor function. What more could we ask?