It's well known that cigarettes can cause lung cancer. And yet, some people smoke like a chimney their entire lives and never get the disease. Now a sweeping search for an explanation has yielded a clue: Three studies have found a marker in the same region of DNA that appears to raise the risk of lung cancer. But the researchers disagree on whether the gene involved directly causes lung cancer or does so by influencing how easily people get hooked on tobacco.
The new research is part of a wave of studies that scan the entire genome of hundreds or thousands of people for 300,000 or more DNA markers, then check whether some markers turn up more often in people with disease than in healthy people. Hunting for such variants for lung cancer, researchers led by deCODE Genetics in Reykjavik, Iceland, scanned the DNA of 11,000 Icelandic smokers. They found a marker on chromosome 15 that is associated with lung cancer and to narrowing of the arteries. But, the team reports in the 3 April issue of Nature, the marker was most frequent in people who smoke more than 30 cigarettes a day, suggesting that it raises the disease risk by making people light up more often.
Two other research teams came to a different conclusion. In a second paper in Nature, a team led by Paul Brennan of the International Agency for Research on Cancer in Lyon, France, compared about 2000 Europeans with lung cancer to an equally large group of healthy people. Although they found a DNA marker in the same area on chromosome 15, the glitch only affected cancer risk, they found--it had nothing to do with smoking behavior. The same is true for a smaller study published online today in Nature Genetics by a team at the M. D. Anderson Cancer Center in Houston, Texas. In all three studies, the risk was about 30% higher for people with one copy of the marker and 70% to 80% higher for people with two copies.
The region where the marker sits contains three genes coding for subunits of the nicotinic acetylcholine receptor, a protein on the cell surface that nicotine molecules latch onto, triggering cell change. There is a mechanism by which these receptors could be directly involved in tumor formation, says Brennan: Lab studies have shown that stimulating cancer cells with nicotine or its metabolites can spur them to form tumors. If that is what's happening, the receptors could be a new target for lung cancer drugs, Brennan adds.
In addition, if the marker is involved in nicotine dependency, as the deCODE paper suggests, the finding is "very important in the whole field of substance abuse," says Nora Volkov, director of the U.S. National Institute on Drug Abuse in Bethesda, Maryland, which helped fund that study. The nicotine receptors, which are active in a part of the brain associated with depression, are not those "classically associated with nicotine dependence," Volkov said, and they could point researchers to new treatments for tobacco addiction.