Why Only Some Smokers Get Lung Cancer?

Smoking is the most potent known cause of lung cancer. The question is: Why do some longtime smokers come down with the deadly disease whereas others escape it? New research points to a genetic culprit that also was fingered as upping a person's likelihood of becoming hooked on cigarettes.

Two new studies link a variation in a gene residing on chromosome 15 (of a person's 23 pairs of chromosomes) to a heightened risk of developing lung cancer; a third study suggests that the same mutation affects a person's tendency to become addicted to smokes and, by extension, develop the dreaded disease. Lung cancer is diagnosed in some 200,000 Americans and kills more than 150,000 each year.

The new research—published in both Nature and Nature Genetics—suggests that people with this genetic flaw have a 30 percent greater chance of developing the often-fatal illness. But the studies differ on the potential added risk of addiction. The findings offer insight into how this particular genetic variation and smoking interact to cause lung cancer. They provide "new targets for starting to think about how to treat drug addiction and, also, of course, for the prevention or treatment of lung cancer," says Nora Volkow, director of the National Institute on Drug Abuse (NIDA) in Bethesda, Md., who was not involved in the study.

The research teams scanned a catalog of 300,000 minute changes in the genome in which a base (unit of genetic material) was either deleted, duplicated or substituted. (Such alterations are known as single nucleotide polymorphisms, or SNPs.) In one study, scientists from Iceland-based biotechnology company deCODE genetics tried to correlate these genetic variants with a person's smoking habits; the other research efforts attempted to tie them to lung cancer.

The deCODE group surveyed 50,000 Icelandic smokers about their habits; using information gleaned from that survey as well as from genomic scans of 40,000 admitted smokers in the bunch, the researchers zeroed in on a variant of the gene CHRNA, which codes for a receptor on nerve cells that can be stimulated by nicotine. The altered version of the gene was more common in the heaviest smokers than it was in the rest of the population. "Nonsmokers have a higher frequency of this variant than smokers that smoke between one to 10 cigs per day," notes neurologist Kári Stefánsson, deCODE's CEO, "because if you smoke and you have this variant, you tend to smoke more than 10 cigs per day."

When Stefánsson's team applied the stats to the incidence of lung cancer, it found that individuals with two copies of the altered gene had a whopping 70 percent greater chance of developing lung cancer; those with one copy had a 30 percent higher risk.

These findings are virtually identical to those of the other studies—one (in Nature) conducted by the International Agency for Research on Cancer (IARC) in Lyon, France (which was based on examinations of some 11,000 volunteers, 7,500 of whom were smokers) and the other (in Nature Genetics) by a team at the University of Texas M.D. Anderson Cancer Center in Houston, which examined 9,000 individuals, some 4,000 of whom were smokers.

Paul Brennan, who led the IARC study, says he initially believed that the risk of getting lung cancer was elevated by the genetic predisposition to become addicted. "The genes made you more likely to smoke, made you likely to smoke more, made you less likely to give up, and therefore more likely to develop lung cancer," he says. But his research showed that, in fact, the gene appeared to independently increase a person's risk of developing the disease—with no link to addiction.

NIDA's Volkow suggests that the gene variant may lead certain individuals to smoke more due to its effect on the brain's reward centers (associated with addictive behavior) and may increase the risk of cancer, too, because it also plays a role in lung tissue function. Epidemiologist Christopher Amos, who led the Texas study, notes that the same nicotine receptor implicated in this study was shown in previous research to prompt tumor growth in other areas of the body, most notably the thymus (an organ located near the lungs that produces immune cells). "Nicotine or its derivatives can stimulate cells to proliferate, participate in new blood vessel development, and also not undergo cell death," he says, which are all characteristics of tumor formation and growth. "So that raises the possibility that there's a direct effect through nicotine in activating cells to go on to become cancerous."

Brennan says more research is needed before the findings can be put into play.

"There's not a public health message here that you can find out what version of the gene you have and decide whether to keep on smoking or not," he says. "You have to bear in mind that there are so many other disease[s] that are caused by smoking."