“Scientists have identified for the first time genetic variations that increase the risk of lung cancer in people who smoke”, The Independent reported today. The Times also covers the story, saying several studies have found a cluster of genes that influence the risk of developing lung cancer, and these could lead to new treatments. The newspapers suggest that the variations in a region of chromosome 15 appear to be sufficiently important to account for nearly one in five cases of lung cancer, and for one in ten cases of peripheral artery disease - a circulatory disorder also linked to smoking.
These, and other newspapers describe recent studies that have shown how a disease that clearly has a strong environmental cause, smoking, may also be affected by genetics. These studies increase our knowledge about areas of the genome that contain potential genetic risk factors for lung cancer and smoking and further studies will be needed to identify exactly how these changes might increase the risk of cancer.
There are several alternative theories as to how these differences in the genetic code might influence the chances of developing lung cancer. One is that they might influence smoking behaviour by making people want to smoke more or by making it difficult for people to quit. The increased consumption of cigarettes would then lead to a higher risk of cancer. The alternative is that the genetic variants play a more direct role in the development of the disease.
These two theories will need further research. However, the primary cause of lung cancer is still smoking, and the most effective way of reducing the risk of lung cancer is to quit.
Where did the story come from?
The news stories are based on two separate journal papers published in Nature, a peer-reviewed journal.
The first paper was authored by Dr Rayjean Hung from the International Agency for Research on Cancer in France and 64 international colleagues. The second paper was written by Thorgeir Thorgeirsson from deCODE genetics and 56 international colleagues. deCODE genetics is a biopharmaceutical company based in Reykjavik, Iceland that researches the genetic basis of common diseases. The studies were supported by grants from multiple sources.
What kind of scientific study was this?
Both papers describe genome-wide association studies.
In the first study, the researchers looked for a genetic influence on the development of lung cancer. The study analysed about 317,000 single-nucleotide polymorphisms (variations in the units that make up the genetic code) of 1,989 people with lung cancer (cases) and 2,625 people without lung cancer (controls) from six central European countries. The researchers were looking for variations that were significantly more common in the cases than in the controls. They confirmed their findings by looking at data from five other lung cancer studies with an additional 2,513 lung cancer cases and 4,752 controls.
The second paper describes a similar study that looked for genetic influences on smoking behaviour and nicotine dependence. They also started by analysing a large number of single-nucleotide polymorphisms in stored blood from 10,995 smokers in their genetic ’bank‘. Concentrating on one variation in genetic code that they had found in the first part of the study, they then looked for its presence in the stored blood of over 30,000 people from Iceland, Spain and the Netherlands, some of who had developed cancer. The proportion of people who had the variation was compared with smokers who developed cancer and smokers who did not.
The researchers also looked for links between the variant and the quantity of cigarettes smoked and a measure of nicotine dependence. The data for the quantity of cigarettes smoked was collected by a standardised smoking questionnaire that asked: “How many cigarettes per day do/did you smoke on average (on most days)?” This means that current smokers answered their current consumption and former smokers refer to their consumption in the past. About 3,000 persistent smokers also answered detailed questionnaires on smoking behaviour to assess whether they fitted international criteria for nicotine dependence.
What were the results of the study?
The researchers in the first study were able to locate a part (locus) of chromosome 15 in an area called 15q25 that was strongly associated with lung cancer. They estimated that this locus could account for about 15% (the attributable risk) of lung cancer cases. Attributable risk is a measure of how many cases of lung cancer could theoretically be prevented if the variant at this locus was changed.
Statistically similar risks were found regardless of smoking status or propensity to smoke tobacco, suggesting that, in contrast to the second study, this data does not support the idea that the locus has a role in determining the number of cigarettes smoked or the chance of nicotine addiction.
The locus contains several genes, including three that encode proteins called nicotinic acetylcholine receptor (nAChR) subunits. These are found in lung tissue and have previously been reported as being linked to nicotine dependence.
In the second study, the researchers identified variations in roughly the same area of chromosome 15, 15q24, that were linked to the amount people smoked. The variation that showed the strongest association lay within the gene encoding one of the nAChR subunits. When they looked at blood samples from people with lung cancer and controls, they found that this variation was more common in people who developed lung cancer and that the presence of the variant was related to the number of cigarettes smoked per day.
What interpretations did the researchers draw from these results?
The researchers of the first study say that their results provide compelling evidence of a locus at 15q25 that gives a predisposition to lung cancer. They say that their research reinforces the idea that nAChRs are potential candidates for disease and targets for new therapies.
The researchers in the second study conclude that their findings show ‘unequivocally’ that there is a link between the variant in the cluster of genes on chromosome 15q24 different to the previous chromosome that encode nAChRs and the amount people smoke and nicotine dependence. They go on to say that this variant does not cause people to start smoking. However, smokers who carry the variant smoke more than those who do not and have higher rates of nicotine dependence.
Both studies claim that variations in genes found on the same chromosome partly account for, or contribute to, the risk of developing lung cancer, smoking and becoming nicotine dependent.
What does the NHS Knowledge Service make of this study?
The studies identified different variants in slightly different areas of the same chromosome, but they are positioned close to each other on the chromosome, and are closely linked to the genes encoding the nAChRs.
Both studies were case controlled. An important feature to consider when assessing their reliability is to look at how well matched the cases are to the controls with which they are compared. When an international sample is used, as in this case, it is possible that the frequency of the variant may be different between or within countries due to other unknown genetic, for example ethnic differences. This effect, known as population stratification, can be a problem which reduces confidence that the results show a true association. The cases and controls in both these studies are not described in enough detail to allow a determination of whether population stratification was a problem here. Both groups of researchers say that the increase in risk demonstrated for this variant must only be seen as an approximation of risk.
All commentators also stress that smoking is still the primary risk factor for lung cancer. It is therefore important to remember that the best thing a smoker can do to reduce their risk of lung cancer, and many other life-threatening diseases, is to quit.
Sir Muir Gray adds...
Analysis by Bazian
Edited by NHS Website
Links to the headlines
The Guardian, 2 April 2008
Metro, 2 April 2008
Daily Mail, 2 April 2008
The Daily Telegraph, 2 April 2008
The Times, 2 April 2008
BBC News, 2 April 2008
The Independent, 2 April 2008
Links to the science
Nature 2008; 452:638-642
Nature 2008; 452:633-637