What makes a smoker prone to cancer?

April 2, 2008 7:20:48 PM PDT
Why do some 90-year-old chain smokers avoid lung cancer, while other people who smoke far less wind up dying of the disease? How can some people light up now and then without getting hooked, while others are addicted practically from their first puffs?The answer, at least in part, may be in your genes.

Scientists have identified certain genetic variations that appear to make people more likely to get hooked on cigarettes and more prone to develop lung cancer.

The findings could someday lead to screening tests and customized treatments for smokers trying to kick the habit.

The discovery by three separate teams of scientists makes the strongest case so far for the biological underpinnings of nicotine addiction and sheds more light on how genetics and lifestyle habits join forces to cause cancer.

"This is kind of a double whammy gene," said Christopher Amos, a professor of epidemiology at the M.D. Anderson Cancer Center in Houston and author of one of the studies. "It also makes you more likely to be dependent on smoking and less likely to quit smoking."

A smoker who inherits these genetic variations from both parents has an 80 percent greater chance of lung cancer than a smoker without the variants, the researchers reported. And that same smoker on average lights up two extra cigarettes a day and has a much harder time quitting than smokers who don't have these genetic differences.

The researchers disagreed on whether the variants directly increased the risk of lung cancer or did so indirectly, by causing more smoking.

The three studies, funded by governments in the U.S. and Europe, are being published Thursday in the journals Nature and Nature Genetics.

The scientists studied the genes of more than 35,000 white people of European descent in Europe, Canada and the United States. Blacks and Asians will be studied soon and may yield different results, scientists said.

They aren't quite sure if what they found is a set of variations in one gene or in three closely connected genes. But the gene variations govern nicotine receptors on cells.

"This is really telling us that the vulnerability to smoking and how much you smoke is clearly biologically based," said psychiatry professor Dr. Laura Bierut of Washington University in St. Louis, a genetics and smoking expert who did not take part in the studies. She praised the research as "very intriguing."

The smoking rate among U.S. adults has dropped from 42 percent in 1965 to less than 21 percent now.

The new studies are surprising in that they point to areas of the genetic code that are not associated with pleasure and the rewards of addiction.

That may help explain why some people can quit and others fail, said Dr. Nora Volkow, director of the National Institute of Drug Abuse in Bethesda, Md., which funded one of the studies.

"It opens our eyes," Volkow said Wednesday. "Not everyone takes drugs for the same reason. Not everyone smokes cigarettes for the same reasons."

One clue is in the location of the just-discovered variants, on the long arm of chromosome 15, Volkow said. It is in an area that, when damaged during tests on animals, makes them depressed and anxious. While some people smoke because it helps them focus or gives them a physiological reward, others do it to stave off depression.

That suggests that adding antidepressants to some smokers' treatment could help them kick the habit.

Bierut said a simple, inexpensive test could be developed to screen people for the variants. Kari Stefansson, lead author of the largest of the three studies, agreed. He is chief executive of deCode Genetics of Iceland, which already does prostate cancer genetic tests.

Such testing could carry risks all its own, bioethicist Arthur Caplan of the University of Pennsylvania warned. People who have been found to have a genetic predisposition to addiction and lung cancer could find it harder to get health or life insurance, or their employer might drop their coverage, he said.

"The good news is that getting these risk estimates will help focus anti-smoking campaigns, and some people will want to voluntarily get into anti-addiction programs early, where they will probably work better," Caplan said in an e-mail. But if such testing is done, it should be voluntary, and the results should be kept private, he said.

Smoking-related diseases worldwide kill about one in 10 adults, according to the World Health Organization.

Among the findings:

- Smokers who get the set of variants from only one parent see a risk of lung cancer that is about one-third higher than that of people without the variants. They also smoke about one more cigarette a day on average than other smokers. This group makes up about 45 percent of the population studied.

- Smokers who inherit the variants from both parents have nearly a 1-in-4 chance of developing lung cancer. Their cancer risk is 70 to 80 percent higher than that of smokers without the genetic variants. They smoke on average two extra cigarettes a day. This group accounts for about one in nine people of European descent.

- Smokers who don't have the variants are still more than 10 times more likely to get lung cancer than nonsmokers. Smokers without the variant have about a 14 percent risk of getting lung cancer. The risk of lung cancer for people who have never smoked is less than 1 percent, said another study author, Paul Brennan of the International Agency for Research on Cancer in Lyon, France.

Brennan and Amos, working on different teams, linked the genetic variation itself - when triggered by smoking - directly to lung cancer. Brennan said the nicotine receptors that the variants act on also can stimulate tumor growth.

But Stefansson said the increased lung cancer risk was indirect - the variants led to more smoking, which led to more cancer.

For Stefansson, the research hits home. His father, a smoker, died of lung cancer. And Stefansson, who doesn't smoke, frequently lectures his 23-year-old daughter "who smokes like a chimney." She acts as if she is immortal and smoking can't kill her, Stefansson said. But his own research shows that her genes are probably stacked against her.


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