Genetic Link to Lung Cancer
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By Stephen Ornes

Genetic Link to Lung Cancer

Does the same piece of DNA both increase risk and make it hard to quit smoking?

By Stephen Ornes


Lung cancer is frequently chalked up to smoking, which is no surprise, because 87 percent of all lung cancer patients in the U.S. have a history of smoking. But what about that rare chain-smoking nonagenarian as hale and hearty as her great-grandchildren?

Many scientists have long suspected a hereditary link to lung cancer: In a 1963 study, smokers whose sibling, parent or child had lung cancer were found to have 2.5 times the risk of smokers without a family history. Now, scientists have identified a genetic link to the disease, which is the most common cause of cancer-related death in the United States.

In each of three independent studies, two published in Nature on April 3 and one online in Nature Genetics on April 2, cancer researchers found a connection between a specific genetic variant, or variation, and increased risk of lung cancer. Combined, the studies involved nearly 35,000 patients, all white, from 18 different countries.

It’s the first time scientists have looked at essentially the whole genome—the collection of all human genes—for clues to lung cancer, says Neil Caporaso, an epidemiologist and medical oncologist at the National Cancer Institute, who did not work on the studies. “That’s what gives these three studies so much power.”

Epidemiologist Paul Brennan, of the International Agency for Research on Cancer in Lyon, France, led one of the studies. Without the genetic variant, he says, a pack-a-day smoker faces about a 14 percent risk of lung cancer. If the smoker inherits the variant from one parent, the risk rises to about 18 percent. If both parents pass on the variant, the smoker’s risk rises to 23 percent. All three studies found the same variant and the same escalation of risk.

A strand of DNA is shaped like a twisted ladder, with its rungs made of molecules called nucleotides. By and large, the order of the nucleotides remains the same for every person. When a single nucleotide differs, however, the location is called a single nucleotide polymorphism, or SNP (pronounced “snip”).

Each of the three research teams analyzed more than 300,000 SNPs on the human genome and zeroed in on the same ones, all on chromosome 15, in subjects with lung cancer. The culprit SNPs show up in genes that have previously been associated with nicotine dependence.

From the research comes a question: Does the variant work directly, by influencing cancer risk at the cellular level, or indirectly, by increasing a smoker’s dependence on nicotine and making it harder to kick the smoking habit?

For Kári Stefánsson, the president of deCODE Genetics in Reykjavík, Iceland, who led one of the studies, the connection between the genetic variant and smoking behavior is clear. “Almost everyone with this variant is more likely to become addicted [to smoking],” he says, and the increase in lung cancer risk is “substantially accounted for by smoking quantity alone.”

Brennan disagrees. “It’s not really to do with addiction,” he says. “Somehow, at the cellular level, [the variant] increased lung cancer. It makes smoking worse, basically.” Brennan cites ongoing studies which suggest that when receptors for nicotine on a cell’s surface are switched on, they engage in carcinogenic behavior, like growing blood vessels and bringing in more oxygen.

Christopher Amos, a genetic epidemiologist at the M. D. Anderson Cancer Center in Houston, led the third study. His data support many of the findings from Stefánsson’s study, but he thinks the variant influences both smoking behavior and a cellular mechanism that increases lung cancer risk. “I don’t see any way that this can be due only to smoking behavior,” he says. “At the end, it has to be cellular.”

All three researchers agree about the need for further investigation. “It’s important to clarify whether this is an addiction effect or more of a cellular effect,” Brennan says. “It’s important for all of us to bring our studies together to identify and answer that question.”