Increased Lung Cancer Risk for Some Smokers

DNA Differences Make Smoking More Dangerous

by Dr. Barry Starr, Stanford University

April 04, 2008

Everyone knows smoking kills. It kills people through various cancers, heart disease, emphysema and in lots of other ways.

But a set of three new studies shows that some people's DNA makes smoking even more dangerous for them. The authors of these studies showed that if a smoker has a certain small difference in their DNA on chromosome 15, then he or she is at a higher risk of dying from lung cancer.

DNA differences on
chromosome 15 increase
a smoker's risk for lung cancer.

Lifetime smokers have about a 15% chance of getting lung cancer. Someone who has never smoked has less than a 1% chance. So smoking makes the average person more than 15 times more likely to die from lung cancer.

The new studies suggest that the situation is even worse for the around 10% of the population with the DNA difference on chromosome 15. If these people smoke, they have a 23% chance of dying from lung cancer. In other words, their risk for lung cancer is more than 23 times that of a nonsmoker.

The studies also looked at some of the other problems smoking can cause. One of the studies showed no increased risk for these smokers for two other common smoking-related cancers, mouth and esophageal cancer. A different study showed that smokers with this DNA difference are at a higher risk for peripheral arterial disease (PAD). This puts them at an even higher risk for heart attacks and strokes.

So it may be that having this DNA difference makes smoking more dangerous in many different ways besides just lung cancer. Of course more dangerous is a relative term. Smoking is wildly dangerous for anyone no matter what his or her DNA is.

The data for the connection between a smoker's DNA and his or her risk for lung cancer is pretty solid. But why those people's DNA leads to more lung cancer isn't at all clear. In fact, the three studies came to different conclusions about why this DNA difference makes smokers more likely to end up with lung cancer.

The Three Studies

How DNA Might Cause Increased Lung Cancer in Smokers

Scientists have found a
DNA difference that
increases a smoker's risk
for lung cancer. Now
they need to figure out why.

The area of DNA that causes the increased lung cancer risk is on chromosome 15. Because of the way the researchers did their studies, they couldn't pinpoint the exact gene involved. So what they did was to look at the genes in the area and guess why these smokers were at an increased risk for lung cancer.

After looking over their data, the researchers came up with different theories. One idea was that these smokers crave nicotine more. Which makes them smoke more.

The other idea was that these people were more susceptible to lung cancer. Somehow something in cigarette smoke more easily triggers the cancer to develop.

Each idea makes different predictions. The first one makes the prediction that people with the DNA difference will smoke more. Another prediction might be that these smokers would be at an increased risk for other smoking related diseases as well.

The second idea predicts just the opposite. Smokers with the DNA difference should not smoke more and only have an increased risk for lung cancer. It might also predict that nonsmokers would be at a higher risk for lung cancer.

Which idea is right? Unfortunately it isn't clear because each side had evidence to support their own idea.

Two of the three studies showed that smokers with the DNA difference smoked more cigarettes than people without the DNA difference. The other study did not find that this was the case.

One study showed an increased risk for PAD which is consistent with these folks smoking more. Another study showed no increased risk for two other smoking related cancers which is consistent with no extra smoking.

Finally, one of the studies showed that nonsmokers with the DNA difference had an increased risk of lung cancer. The other studies showed no increased risk.

Right now no one can say which theory is correct. Or if there is a different reason altogether. All the scientists can say is that a particular DNA difference is associated with increased lung cancer risk.

To really find out why these smokers get lung cancer more often, the researchers will need to nail down which gene is different in these people. And figure out how that difference affects how a cell reacts to cigarette smoke.

The authors haven't found the exact gene involved yet because this was the first phase of a gene hunt. This was something called a genome wide association study or GWAS.

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Genome Wide Association Study

Scientists use microarrays to
look at hundreds of thousands of
DNA differences all at once.

A genome wide association study or GWAS is really just a first pass at trying to figure out why two different groups of people are different at the DNA level. Once this first pass is done, there is still a lot more work to do.

In the next step, the DNA around an identified region is looked at in much finer detail. This lets the researchers pinpoint which gene is affected.

The final steps are to understand how that gene works and why when the gene works differently, a disease can happen. (This works for traits or anything else measurable that is due to DNA as well.)

Let's look at these three studies in detail to get an idea of how this can work.

Each study started out with a large group of smokers. They collected thousands of smokers' DNA and figured out what each looked like at many, many different spots.

For example, all of the studies looked at over 300,000 different parts of the smokers' DNA. They all looked at around the same amount of DNA because they used the same microarray product to do their research. This sounds like a lot of DNA but it is really a small part of the 6 billion letters that make up human DNA.

To get a meaningful result, the researchers needed to look at the DNA of a lot of smokers. One study looked at over 10,000 Icelandic smokers. The other studies looked at either 2,500 or 4,000 different smokers.

The researchers then compared the DNA of smokers who got lung cancer with those that did not. And they looked for significant differences.

Each group came up with a set of DNA differences. The next step is to look at just these differences in many other smokers' DNA to settle on the really critical ones. Each group arrived at the same DNA differences on chromosome 15.

Finding the gene that explains the
increased lung cancer risk will
be very difficult.

Now just because they came up with the same DNA difference that doesn't mean it is the difference that causes the problem. They all used the same technology to study their samples and so came up with the same DNA difference.

This tells us that the DNA difference is almost certainly pointing to this region of chromosome 15 as being important. What it isn't doing is telling us why.

Figuring out why these smokers got lung cancer more often isn't so clear cut. There are all sorts of experiments researchers can do now that they have identified this DNA difference.

Researchers can look for the DNA difference in different groups and try to associate it with different diseases or traits. Or they can try to find other connections within the same groups. These researchers did both of these things.

One group looked for the DNA difference in people with different cancers or nonsmokers. Another group looked to see if the smokers they looked at suffered from PAD as well. All the groups also looked to see if smokers with the DNA difference smoked more. And they came to different conclusions about this.

These studies are important but the best way to figure out what is going on is to identify the gene that is responsible for the increased risk. Then researchers need to figure out why people end up with lung cancer when that gene isn't working properly. And finally, the researchers need to figure out how to use that information to help smokers.

This will be much harder and much less splashy than the preliminary results presented in these studies. But if anything, it is even more important.

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Content provided by the Department of Genetics, Stanford University.