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Studies Find Genetic Variation Linked To Lung Cancer Risk April, 2008

A trio of papers published Wednesday identifies for the first time a specific genetic variation linked to increased risk of lung cancer, but the studies disagree about whether the risk is elevated because the gene variant increases smoking behavior or addiction to nicotine.

The studies, conducted by three independent research groups and published in the journals Nature and Nature Genetics, all found that increased lung cancer risk was associated with a gene variant on chromosome 15. The variant increased the risk by as much as 80% among smokers who had two copies of the variation and by about 30% if they had one copy. However, smoking far outweighs a genetic predisposition in developing lung cancer, the researchers said.

The genetic variants identified in these studies appear to be related to genes that control receptors that bind nicotine and acetylcholine. These receptors have been found in previous work to be linked with nicotine addiction.

"It's pointing the finger at nicotine, but it's not saying it's the only factor," said Christopher Amos, a professor of epidemiology at M.D. Anderson Cancer Center in Houston and an author of the paper published in Nature Genetics.

The gene variation also appears to be linked to smoking behaviors. One study carried out by researchers at deCode Genetics Inc. (DCGN) in Iceland showed that the high-risk variant was associated with higher smoking quantity, greater nicotine dependence and difficulty with stopping smoking, but doesn't appear to make it more likely that an individual with the high-risk variant will begin to smoke.

"If you try it, you're more likely to do it more," said Kari Stefansson, chief executive of deCode and senior author on one of the papers published in Nature. "If you smoke, you become hooked. It makes you more likely to repeatedly expose yourself."

But it's not clear that individuals with the high-risk gene variant develop cancer more frequently because they smoke more or have a harder time quitting, said Matthew Meyerson, associate professor of pathology at Harvard Medical School's Dana-Farber Cancer Institute, who wasn't involved in any of the studies.

Better understanding how the genes affect actual smoking behavior may have implications for better identifying people who may become more easily addicted to smoking or to nicotine and have more trouble quitting smoking, Amos said. But it doesn't mean that people with the lower risk variant are protected from developing lung cancer if they choose to smoke.

"The public health implications don't change at all," said David Hunter, a professor of epidemiology at the Harvard School of Public Health, who wasn't involved in any of the studies but who wrote a commentary on the studies in Nature. "The recommendation that people who don't smoke shouldn't start, and people who do smoke should stop remain unchanged."

Stefansson said his company will likely offer a genetic test for smoking risk at some point for people who are curious, but he is "ambivalent" about its clinical usefulness.

"If we in the end will offer this test, we will offer it with a firm statement that even if you come out of it (without the high risk variant), it is a million miles away from being a green light telling you to smoke," he said.

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