Smoking causes lung cancer. That much is known. But three new studies published today suggest that genes might play a role in why some longtime smokers get the deadly disease and others do not.
The scientists say these common genetic variations might also make smokers more likely to become addicted to tobacco and to smoke more cigarettes.
The findings, which several experts said mark the first time that a genetic variation has been linked to lung cancer, could lead to a greater understanding of how smoking and genes interact to cause the disease.
"I've been calling it the double whammy gene," said Dr. Chris Amos, a genetic epidemiologist at the M.D. Anderson Cancer Center in Houston and lead author of one of the studies. "It increases your lung cancer risk, and it also makes it hard for you to quit smoking, makes you more dependent."
Researchers also said the discovery could lead to the development of customized smoking-cessation programs for those whose genes might make it more difficult to stop on their own.
Smokers and former smokers have a 15 percent greater risk of developing lung cancer - the deadliest cancer - than nonsmokers do, researchers said. But smokers who got the genetic variations from both parents have an 80 percent greater risk of developing lung cancer than smokers without them, the studies show.
People who never smoked but had the genetic quirk were not more susceptible to lung cancer.
"Smoking - it's the overwhelming risk factor whether you have one or two or no variants," Dr. Kari Stefansson, chief executive officer of deCODE Genetics in Iceland and author of the largest of the three studies, said during a conference call this week.
About 50 percent of Caucasians of European descent have the genetic variation, researchers found. Genetic studies have not been done on other ethnic groups.
Scientists cautioned yesterday that even if widespread testing could be done for the genetic variations, the public health advice would not change: People who don't smoke shouldn't start, and people who smoke should quit.
If a smoker learned that he did not have the variation, it "should not be any comfort," said Dr. Norman Edelman, chief medical officer for the American Lung Association and a professor of medicine at the Stony Brook University Medical Center in New York. "They should not think ... 'Oh, well. I can smoke with impunity. I'm OK.' That's not the way it works."
The studies - led by researchers in France, Iceland and the United States - are being published in the journals Nature and Nature Genetics.
The three groups looked at 35,000 people and came up with similar conclusions about the same region on chromosome 15, a spot known to house nicotine receptors. Two of the research groups said the link is directly between lung cancer and the genes; the other found an indirect route.
The researchers from Iceland said there is a correlation between the genetic variation and nicotine dependence and the amount of smoking. Being a carrier doesn't make people start smoking, but it makes them smoke more - one to two more cigarettes a day - and makes it tougher for them to quit. Those researchers concluded that those factors - which are genetically based - probably lead to the increase in risk of lung cancer.
Paul Brennan of International Agency for Research on Cancer in Lyon, France, author of another study, said he agreed with that at first but was convinced later that "the genes primarily increase the risk of lung cancer by driving forward the process at the cellular level."
Nicotine could be the environmental trigger that stimulates tumor growth in those with the variation, he said.
Dr. Stephen J. Chanock, chief of the laboratory of translational genomics for the National Cancer Institute, said the studies - even in their somewhat differing conclusions - bring a better understanding of the biology of lung cancer.
"These studies are all pointing in the same place," he said. "They point to places in the genome we didn't know about."
Future researchers will look at this region and determine whether it pertains to smoking habits, lung cancer or a combination of the two.
"The jury is still out," Chanock said.
"With respect to lung cancer, every extra bit we learn helps," said Dr. David J. Hunter, an epidemiologist at the Harvard School of Public Health.
Smoking has been declining in the United States. In 2006, 20.8 percent of U.S. adults were cigarette smokers, according to the Centers for Disease Control and Prevention, less than half the percentage in 1965.
Airplanes, workplaces, restaurants and bars in many regions have gone smoke-free. But the residual effects of the era when smoking was more prevalent remain. Lung cancer kills more people than any other cancer. More than 160,000 Americans die of the disease each year.
Those who might have trouble quitting smoking because of their genes could get extra help in the future if researchers can build on the findings of the studies. Scientists might be able to find new targets for medications or design programs better suited to those who are more easily addicted.
"Can we use this information to help people quit something that's bad for them?" Amos said.
Some researchers said they also hope that a future test for a genetic link to lung cancer could help doctors decide which tools - such as CT scans - should be used on which patients, such as those with increased risk.
Researchers say they worry that smokers might feel they have an excuse to keep smoking if they learn they don't have the genetic predisposition for lung cancer.
Smoking is a risk factor for a number of other illnesses, including pancreatic cancer, heart disease and complications from diabetes.