Genes, Smoking, and Lung Cancer

Imagine this kind of warning on a cigarette package: Quitting smoking now greatly reduces serious risk to your health, particularly if your DNA is mutated at the 15q24 locus. Would you get tested for this mutation?

Right now, there is no such test. But someday, there might be.

Years of study and a mountain of evidence point to tobacco smoking as the single most important risk factor for lung cancer. Nonsmokers (people who have smoked fewer than 100 cigarettes over the course of their lives) have less than a 1% chance of ever developing lung cancer. Smokers, on the other hand, have about a 14% chance of developing lung cancer at some point during their lifetime—that means their risk is more than ten times higher than that of nonsmokers! But is smoking the only factor that increases a person's risk of lung cancer? The short answer is no, as genetics has been shown to play a role as well.

So, what specific genetic factors are involved in an increased risk of lung cancer? In recent years, three independent groups of international scientists have identified a region on chromosome 15 that, if mutated, dramatically increases a smoker's risk of developing lung cancer by another 30% to 80% (giving smokers who carry this mutation an overall lung cancer risk of about 20% to 23%), depending on whether an individual has one or two copies of what the researchers are calling the 15q24 susceptibility locus (Amos et al., 2008; Hung et al., 2008; Thorgeirsson, et al. 2008). In general, a susceptibility locus is a region on a given chromosome where mutations that affect one or more genes are suspected to be present, based on statistical evidence. These mutations can be located in coding segments of one or more genes, therefore directly affecting gene products, or they may be found in sequences that control gene function (known as regulatory regions).

Altogether, the three research groups that studied the 15q24 susceptibility locus surveyed more than 35,000 people across Europe, the United States, and Canada. Data were collected on both lung cancer patients and people without lung cancer, as well as on both smokers and nonsmokers. All three groups of researchers eventually zeroed in on the same section of DNA: the long arm of chromosome 15, a region that encodes several genes, including a few that code for nicotinic acetylcholine receptors. These receptors bind to nicotine and nicotine derivatives and are found on cells in the nervous system, in the lungs, and elsewhere in the body. Moreover, all three groups of researchers used the same basic technique in isolating this portion of chromosome 15: genome-wide association studies (GWAS).

Scientists have used GWAS to discover over 100 regions of the genome now known to be associated with various fairly complex human disorders (i.e., complex with respect to the number of genes involved and the amount of interaction between those genes and the environment), including diabetes, heart disease, and breast, colorectal, and prostate cancers. In the three lung cancer studies, the researchers used GWAS to scan the genome, and they found associations between single nucleotide polymorphisms (SNPs) and lung cancer on chromosome 15. In other words, the researchers found that certain SNPs are more common in people with lung cancer. (SNPs are DNA sequence variations that result from one nucleotide base being substituted by another; scientists estimate that as much as 90% of all human genetic variation is in the form of SNPs.)

In one of the three studies, the scientists conducted genome-wide SNP genotyping on 14,000 Icelandic smokers and then evaluated associations between SNP variation and lung cancer, as well as between SNP variation and the number of cigarettes smoked per day. These studies yielded two interesting findings. First, the researchers noted a significant association between variation at the 15q24 locus and lung cancer; second, they found a significant correlation between that same variation and the average number of cigarettes an individual smoked each day. This second finding led the researchers to argue that there is genetic basis for both lung cancer and nicotine dependence. In other words, based on the researchers' interpretation of the evidence, not only do genes ("nature") play a causal role in lung cancer, alongside the huge causal role that smoking ("nurture") has long been known to occupy, but they also seem to have something to do with why people become addicted to tobacco in the first place.

The other two groups of scientists agreed with some of the first group's findings; specifically, they also concluded that SNP variation is correlated with lung cancer risk and that smokers with a particular type of SNP genotype have a substantially greater risk of developing lung cancer than individuals with other genotypes. However, these two sets of scientists came to a much different conclusion than the first group regarding the genetic basis for tobacco addiction. While these scientists did not actually investigate the specific roles of any of the genes in the 15q24 region, they argued that the evidence provided sufficient reason to speculate that the altered genes on 15q24 most likely play a direct causal role in lung cancer by interfering with nicotine acetylcholine receptors and stimulating tumor growth (as opposed to an indirect causal role related to nicotine addiction). For example, in the study from one laboratory, which involved about 12,000 individuals from several central European countries, the scientists found a weak but still statistically significant association between variation in 15q24 and lung cancer in nonsmokers (Hung et al., 2008). The authors speculated that the presence of this association in both nonsmokers and smokers suggests that the association between the gene and lung cancer is direct and has little to do with nicotine addiction. If the association were mediated through nicotine addiction, the scientists reasoned, they shouldn't have found the association in nonsmokers. The researchers further argued that a lack of correlation between genes in the 15q24 region and other smoking-related cancers (e.g., head and neck cancer) also suggests that the mechanism is probably not related to nicotine addiction. If it were, they reasoned, there should be an increased risk associated with 15q24 for those other cancers as well.

Whether the association between the 15q24 susceptibility locus and lung cancer is direct (i.e., there is a gene in that region that causes lung cancer) or indirect (i.e., there is a gene in that region that causes tobacco addiction, which in turn causes lung cancer) remains to be determined. Until scientists actually focus on specific genes in the region and start investigating whether and how these genes function in the nicotine receptor (and other) molecular pathways, the most that the authors of these studies can do is speculate on causality. However, the opposite conclusions reached by the different research teams do underscore the importance of conducting large-scale genetic studies that also take into account environmental factors, such as the number of cigarettes a person smokes per day. As described in a Nature commentary that accompanied publication of the three studies, the excitement of the genome-wide rush to find links between SNPs and disease too often leads scientists to overlook potentially valuable information that could help disentangle some of the "nature versus nurture" knots that pervade much of the evidence around complex diseases like cancer. In the words of the commentators (Chanock & Hunter, 2008):

These are the first GWAS to attempt to identify the genetic component of a disease that has such an overwhelmingly strong environmental cause. They signal the need for greater methodological rigour in attempts to account for both the genetic and environmental causes that we think underlie most diseases.

While there is much more science to be done to separate out and better understand what roles, if any, nicotine addiction and nicotine receptors play in lung cancer, at the very least, the organizers of these studies all agree that there is indeed a greater risk of developing lung cancer among smokers who carry a certain type of SNP variation on the long arm of chromosome 15. These scientists also agree that just because the risk is greater for genetic carriers of the susceptibility locus, this doesn't mean that noncarriers are immune from disease. Smoking is still the number-one cause of lung cancer in humans. Even if a smoker were to test negative for the 15q24 susceptibility locus, smoking could still seriously damage his or her health. Remember, even smokers without the locus have a tenfold greater risk of develop lung cancer than nonsmokers do. In other words, all smokers are at risk of lung cancer, but some smokers are a greater risk than others.

If every smoker is at risk for lung cancer, then why get tested for the susceptibility locus? Given the public health messages we already hear about how smoking can harm our health, will smokers who disregard those messages be any more likely to change their habits if they know that their risk of lung cancer is 23 percent (if both chromosomes have the susceptibility locus) instead of 15 percent (if neither chromosome has it)? These types of questions will likely be the subject of public debate for years to come.