Published online 2 April 2008 | Nature | doi:10.1038/news.2008.733

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Genetic link for lung cancer identified

Studies suggests that cancer risk is not just down to lifestyle.

Amongst smokers, genetics may raise the risk of lung cancer by 80%.Punchstock

Three independent genetic studies have found some of the strongest evidence yet that your genes influence your risk of developing lung cancer.

Lung cancer, the most common killer cancer in the world, is largely caused by smoking. Tobacco is thought to be responsible for about 5 million premature deaths every year and smoking is still clearly the largest risk factor. But the new results suggest that, amongst smokers, some people may be as much as 80% more at risk than others thanks to their genes.

People who have never smoked might also have a slightly increased risk of developing lung cancer and similar problems, although the three studies disagree on whether this is actually the case. It is not clear whether the genetic effect occurs independently of smoking, or whether the genes raise the risk of cancer by exacerbating nicotine addiction.

The cancer region

By scanning the entire genomes of lung-cancer patients and healthy controls, the three research teams all identified a region on chromosome 15 that seems to influence the likelihood of developing cancer. People possessing a certain set of mutations at this genetic location are more likely than others to have the disease.

About 50% of the general population carries a single copy of this cancer gene variant, members of the three research groups suggest. Data from all three studies — some of which did not include non-smokers — show that possessing this single copy raises the risk of lung cancer by about 30%.

What's more, another 10% of the population is likely to carry two copies of this set of mutations, raising cancer risk by as much as 80% relative to people with equivalent lifestyles without the cancer-linked gene variant.

Smoking is still the mostly significant contributor to lung cancer, says Kari Stefansson of deCODE Genetics in Reykjavik, Iceland, who led one of the studies1, which featured almost 11,000 Icelandic smokers. "Just smoking itself is the overwhelming risk factor," he says.

Smoking still kills

A typical smoker who refuses or fails to give up has a roughly 15% risk of lung cancer over their lifetime. But with two copies of the genetic variant, this rises to 23%. In contrast, someone who has smoked fewer than 100 cigarettes in their entire life has a less-than-1% chance of developing the disease.

The researchers disagree over whether non-smokers who possess the genetic risk factor have an increased risk of developing lung cancer. The method used by all three groups makes it difficult to tell, because the technique, called a genomewide association study, hunts 'blindly' for genetic mutations correlated with certain diseases, but provides no information about the mechanisms that cause the disease.

Paul Brennan of the International Agency for Research on Cancer in Lyon, France, who led a study involving almost 2,000 European cancer patients2, says that his team found no evidence that the genetic effect depends on nicotine intake, so the genes may raise cancer risk independently of smoking.

Brennan and his colleagues found that the genes had no effect on the risk of other smoking-related cancers, such as mouth cancer. "Any association with nicotine must must be modest," he claims, although he adds that "a lot more work is required in this area."

Non-smokers at risk too

A third study3, involving almost 6,000 cancer cases and led by Christopher Amos of the University of Texas M. D. Anderson Cancer Center in Houston, also found that the gene variants raise cancer risk independently of smoking behaviour.

Stefansson, in contrast, believes that the genes promote cancer by making people more vulnerable to nicotine addiction. This view is supported by the fact that the genes for the brain's nicotine receptors are found in the same region of chromosome 15 as the genetic mutations.

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People in Stefansson's study group tended to be more heavily addicted to smoking if they had more copies, or 'alleles' of the gene variants. "In our study, we found if you have one allele you smoke about one more cigarette per day; if you have 2 alleles you average two more cigarettes per day," he says.

Cancer campaigners stress that smoking is still the number-one risk factor for the disease. "It’s important to remember that the best thing a smoker can do to reduce their risk of lung cancer and a host of other life-threatening diseases is to quit," says Lesley Walker, director of cancer information at British charity Cancer Research UK. A smoker who quits in middle age can expect their lifetime cancer risk to fall to less than 10%. 

  • References

    1. Thorgeirsson, T. E. et al. Nature 452, 638-641 (2008). | Article |
    2. Hung, R. J. et al. Nature 452, 633-637 (2008). | Article |
    3. Amos, C. I. et al. Nature Genet. doi:10.1038/ng.109 (2008).
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