Although 80% of lung cancer cases are attributable to smoking, scientists have long known that genetics play a role. Family studies have shown that having a parent or sibling with lung cancer doubles or triples the odds of developing the disease.
Yet finding the genes that predispose people to lung cancer has been difficult.
The studies -- two in the journal Nature and one in Nature Genetics -- implicate a genetic variation located near a cluster of genes on chromosome 15 that are involved in the body's response to nicotine.
People who inherit the variation from one parent have a 30% greater chance of developing lung cancer, the published studies said. Those who inherit the variation from both parents face an increased risk of 70% to 80%.
The discovery may help to explain why some smokers don't develop lung cancer and why some occasional smokers don't become addicted, researchers said.
Smokers generally face a 15% chance of developing lung cancer; those with one copy of the genetic variation have about the same risk. Smokers who inherit two copies face about a 1 in 4 chance of developing lung cancer.
The groups detected the variation by analyzing the genomes of more than 35,000 smokers and former smokers, and a smaller number of nonsmokers, almost all of whom were from Europe, Canada and the United States.
About half of the people of European descent have one copy of the variation, scientists said, which is believed to be much less common in people of African or Asian descent.
The three studies were divided on whether the genetic variant directly increased the risk of lung cancer or did so indirectly by predisposing people to smoking.
One of the teams linked the variation to smoking addiction. Study author Kári Stefánsson, chief executive of Iceland-based deCODE genetics, said smokers who had inherited one variant smoked an average of one more cigarette a day than other smokers. Smokers who had inherited two copies smoked an average of two extra cigarettes a day, he said.
People with the variant also had a more difficult time quitting, he said.
Stefansson said it was the extra cigarettes, and not the gene itself, that led to lung cancer. His group estimated that the variation was indirectly responsible for 18% of lung cancers and 10% of cases of peripheral artery disease, which is also linked to smoking.
"Lung cancer is almost certainly environmentally induced, and we have found the variant that pulls us toward that environment," he said.
The other two teams linked the M.D. Cancer Center variation directly to the disease. Paul Brennan of the International Agency for Research on Cancer in Lyon, France, who is an author of one of the three studies, said there was no connection between the variant and smoking addiction. Nonsmokers with a variant had a higher risk of lung cancer compared with nonsmokers without one, Brennan said.
Christopher Amos of the University of Texas M.D. Anderson Cancer Center in Houston, lead author of another study, looked at a larger group of nonsmokers and found no increased risk of lung cancer in those with a variant.
Amos and Brennan, who worked on different research teams, said it was possible that the genetic variant was triggered by substances in tobacco smoke.
People who have never smoked have a less than 1% chance of getting the disease.
Stefánsson said his company, which sells genetic tests, would eventually begin to market a lung cancer screening tool based on the study results.
Stephen J. Chanock of the National Cancer Institute and David J. Hunter of Harvard University, the authors of a commentary also published in Nature, said such a test could be used to assess the success of cessation programs in people predisposed to smoking.
But Chanock and Hunter warn that the test may delude people without the variant into thinking that they are immune to the health risks of smoking, which besides lung cancer include heart disease and pulmonary disease.
Last Mod: 06 Nisan 2008, 00:08