Gene Variants Linked to Lung Cancer Identified

WEDNESDAY April 2, 2008 -- Scientists have pinpointed an area on chromosome 15 that has three nicotine receptor genes that appear to increase the risk for lung cancer.

This finding offers yet more evidence that lung cancer is tied to genetics and not just smoking. However, whether these gene variants represent a direct risk for lung cancer and increased susceptibility to smoking isn't clear, according to two studies published in the April 3 edition of Nature and one published in the April 2 online edition of Nature Genetics.

In the first study, researchers show a link between gene variants that increase one's affinity for smoking and the risk for lung cancer.

"We started by looking at the impact of gene variants on smoking behavior," Dr. Kari Stefansson, president of deCODE Genetics Inc., said during a Tuesday teleconference on the research.

In the study, Stefansson, looked at 14,000 smokers and found nicotine receptor genes that affect how much one smokes. These genes appear to influence the quantity of smoking as well as smoking dependence.

"In addition, we found a gene variant which confers nicotine dependence also confers a fairly substantial risk of lung cancer and peripheral arterial disease," Stefansson said. "So people who have inherited this variant from one parent have a 30 percent greater risk of developing lung cancer."

This variant is common in about 40 percent of the population, Stefansson said. "For those who've inherited the variant from both parents, their risk of developing lung cancer is 70 percent greater than those who haven't inherited the variant," he noted.

In a second study, led by Paul Brennan from the International Agency for Research on Cancer in Lyon, France, researchers looked at 11,000 people, about 4,500 of whom had lung cancer.

"Variations in the region of chromosome 15 were more common in cases of lung cancer than controls, far above what we would have expected by chance," Brennan said during the teleconference. "There was about a 30 percent increased risk for those who have one variant and about an 80 percent increased risk for lung cancer for those with two variants."

These variants are in genes that affect nicotine addiction, but they are also involved in making cells increase in number, which may increase the chances of development of a tumor, Brennan said.

While the association between nicotine addiction and increased smoking and lung cancer seemed a likely explanation, Brennan's team rejected this hypothesis. "We tended to conclude that the association was primarily not due to tobacco addiction," he said.

Brennan's team found that how much one smoked or for how long had no effect on the risk for lung cancer. In addition, the gene variants were found among people who never smoked.

The researchers also looked at people who had other diseases associated with smoking but could not find an association between a gene variant and these diseases, Brennan said. "These gene variants appear to be specific for lung cancer and not other diseases strongly associated with tobacco," he said.

In the third study, from Nature Genetics, Dr. Christopher Amos of the M.D. Anderson Cancer Center in Houston and his colleagues analyzed about 3,000 patients with lung cancer who had been smokers.

As in the other studies, Amos said his group also found a 30 percent increased risk among individuals with one variant and about 80 percent increased risk for lung cancer among the 10 percent of the population that had two copies of the variant.

"What is remarkable about our studies is how similar the results are with respect to lung cancer risk," Amos said during the teleconference.

Amos's team did find an association between these gene variants and smoking behavior. "But the association is much higher with the risk for lung cancer than for smoking," Amos said. "There really does seem to be an independent risk factor for lung cancer in this chromosome region."

One expert thinks these studies alone cannot determine whether increased risk of lung cancer associated with gene variants on chromosome 15 is due to smoking or some other cause.

"Because there is such a powerful environmental effect of smoking on lung cancer, we can't say for certain whether the association in that part of the genome is related directly to smoking or to the cancer process itself or an interaction of the two," said Dr. Stephen J. Chanock, chief of the Laboratory of Translational Genomics at the U.S. National Cancer Institute and co-author of an accompanying Nature editorial.

Chanock thinks the increased risk for lung cancer results from interaction of smoking and the variants' role in cancer.

"This region is contributing to smoking behavior, and it may also contribute to the process that leads cells astray to develop cancer, particularly in the lungs," Chanock said. "The question is, which is it driving more, lung cancer or the smoking."

More information

For more about lung cancer, visit the American Lung Association.

Posted: April 2008


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