Topic: Genes
Genetics and lung cancer
Smoking out the smoking geneApr 3rd 2008 | NEW YORK From The Economist print edition
Your genes may control how much you smoke¬and how likely you are to get lung cancer as a result
THAT smoking causes lung cancer is well established. But what causes smoking? This is the question at the heart of a study published in Nature by a group of researchers who work at deCODE, an Icelandic genomics company. They do not, quite, answer it. But they do think they have the answer to the related question of why some smokers smoke in moderation whereas others are rarely found without a fag in their hands¬and thus why some people are, genetically speaking, more susceptible to lung cancer than others.
That answer lies in part of human chromosome 15, and depends on what is known as allele T of SNP rs1051730. A SNP, or single-nucleotide polymorphism, to give its full name (the short version is pronounced “snip”), is a place where genomes routinely differ from one another by a single genetic letter. In this case, the variation happens inside a gene for one of the receptor molecules that nicotine attaches itself to when it produces its buzz. Based on a study of 13,945 Icelandic smokers, deCODE's researchers showed that having a T in the appropriate part of the gene correlates very strongly indeed with being a heavy smoker. The team estimates that the chance of their being wrong is less than one in a thousand trillion.
Not surprisingly, having the T variant also correlates with the chance of a smoker getting lung cancer. Each copy (there may be none, one or two, since one can come from a person's father and one from his mother) increases that chance by 30%. The T variant does not, however, increase the likelihood that someone will take up smoking in the first place. That is either a matter of free will or, if it is genetic, is controlled by genes somewhere else.
It all looks neat and simple¬and extremely plausible. Genes promote smoking; smoking promotes cancer. However, it might be wrong. For another paper in Nature, and a third in its sister journal Nature Genetics, report similar studies that have drawn rather different conclusions.
Model T?
Paul Brennan and Christopher Amos both agree that something significant is going on in the part of chromosome 15 studied by deCODE. But they have concluded that genetic variation there acts directly on a person's susceptibility to lung cancer, rather than acting indirectly by modifying his smoking behaviour. That does not mean the gene or genes in question actually cause lung cancer. Rather, it means that they amplify the effects of smoking instead of the amount of smoking.
Like deCODE, both Dr Brennan (who works at the International Agency for Research on Cancer, in France) and Dr Amos (who works at the University of Texas) identified rs1051730 as an important SNP. Unlike deCODE, though, both think a second SNP, rs8034191, is involved as well. That, and the fact that the region of chromosome 15 under scrutiny has two other nicotine-receptor genes in it, suggests the situation may indeed be more complex.
On top of this, Dr Brennan and Dr Amos both used a different method from deCODE's. They compared lung-cancer patients directly with otherwise similar cancer-free smokers, in what is known as a case-controlled study, and concluded that genetic variants in the nicotine-receptor-rich part of chromosome 15 are changing not smokers' behaviour, but their susceptibility to cancer. Moreover, Dr Brennan also claims to have discovered an increased susceptibility to lung cancer in non-smokers with the relevant SNPs, though his sample size is small and his result is not supported by Dr Amos's work.
These contradictory conclusions are both puzzling and intriguing. DeCODE has one further piece of evidence in its favour. Besides the correlation with lung cancer, the T variant also seemed to correlate with peripheral arterial disease, another common side-effect of smoking. On the other hand, the firm also acknowledges that the link it thinks it has discovered does not account for the whole of the risk of smoking-induced lung cancer. What is not in doubt, however, is that there is some sort of a link between genetics and lung cancer.
That raises interesting issues, particularly as genetic testing becomes easier. DeCODE has already announced it will add rs1051730 to the standard screen it offers to those who wish to know their susceptibility to diseases. The day is not far off, therefore, when those who take the essentially irrational decision to start smoking tobacco will be able to find out in advance exactly how foolish they are being.
Can't quit smoking? Blame your genes
The Associated Press
April 3, 2008Scientists say they have pinpointed a genetic link that makes people more likely to get hooked on tobacco, causing them to smoke more cigarettes, making it harder to quit, and leading more often to deadly lung cancer.
The discovery by three separate teams of scientists makes the strongest case so far for the biological underpinnings of the addiction of smoking and sheds light on how genetics and cigarettes join forces to cause cancer, experts said. The findings also lay the groundwork for more tailored quit-smoking treatments.
"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.''
Greater cancer risk
A smoker who inherits this genetic variation 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 three studies, funded by governments in the U.S. and Europe, is being published Thursday in the journals Nature and NatureGenetics.
The scientists surveyed genetic markers in more than 35,000 people in Europe, Canada and the United States, zeroing in on the same set of genetic differences. They aren't quite sure if what they found is a set of variations in one gene or in three closely connected genes. But they said the result is the same: These genetic quirks increase the risk of addiction and lung cancer.
The studies' authors disagreed on whether the set of variants directly increased the risk of lung cancer or did so indirectly by causing more smoking that led to the cancer.
The genetic variations, which encode nicotine receptors on cells, could eventually help explain some of the mysteries of chain smoking, nicotine addiction and lung cancer that can't be chalked up to environmental factors, brain biology and statistics, experts said. These oddities include why there are 100-year-old smokers who don't get cancer and people who light up an occasional cigarette and don't get hooked.
In the last 40 years, the rate of adult Americans smoking has been cut from 42 percent in 1965 to less than 21 percent now.
The new studies point to surprising areas of the genes not associated with pleasure and addiction rewards. That may help explain why people have trouble quitting, said Dr. Nora Volkow, director of the National Institute of Drug Abuse in Bethesda, Md., which funded one of the studies. Eventual testing for the genetic variants could lead to custom treatments for quitting smoking.
"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, and a genetics and smoking expert who did not take part in the studies. She praised the research as "very intriguing.''
The studies mostly looked at smokers and ex-smokers - although two of the studies also looked at several hundred nonsmokers. The research only involved white people of European descent. People of Asian and African descent will be studied soon and may yield quite different results, scientists said. Smoking-related diseases worldwide kill about one in 10 adults, according to the World Health Organization.
The studies show on average the consequences of the set of variations in the alphabet of genetic code that people inherit from each parent:
Can't quit smoking? Blame your genes
Smokers who get the set of variants from only one parent see a risk of lung cancer that is about one-third higher than people without any 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 almost a one in four chance of developing lung cancer. Their risk is between 70 and 80 percent higher than the cancer risk of other smokers without the genetic variants. They smoke on average of two extra cigarettes a day, and have a 45 percent higher risk of peripheral artery disease. 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 overall have about a 14 percent risk of getting lung cancer. By comparison, 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 onCancer 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 acton also can stimulate tumor growth.
Brennan's study also found that lung cancer risk for nonsmokers with the variants was higher than for those without the variants. However, his small sample size of nonsmokers requires further study. Amos' study didn't find increased lung cancer risk for people with the set of variants who have never smoked.
But Kari Stefansson, lead author of the largest of the three studies and chief executive of deCode Genetics of Iceland, said the increased lung cancer risk was indirect, and that the variant caused more addiction and more smoking. It was the extra cigarettes from increased daily smoking and the inability to quit that contributed to the higher cancer risk, Stefansson said.
"It's very likely that in the end there's going to be a test and this is going to be folded into a panel of tests for the risk of cancers,'' said Stefansson, whose company already does prostate cancer genetic tests. The tests will lead to better treatments, but probably not prevention of smoking, he said.
Stefansson and others emphasize that people without the variants should not take that genetic finding as a green light to smoke.There are other smoking-related diseases and they would still be a thigh risk of lung 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 like 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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