New Smoking Gun?

Teams come together to target the genes behind lung cancer, but the hunt is far from over.

Image modified from © Alfred Pasieka / Photo Researchers, Inc.

Scientists have known for years why more than 1 million people die of lung cancer every year—smoking. Thus, when it came to looking for a genetic basis to lung cancer, “there was a lot of skepticism” about the importance of such research, says molecular epidemiologist Neil Caporaso of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI).

But evidence that lung cancer tended to run in families suggested that there might be a hereditary component of the disease after all, and early studies identified genes that correlated with an increased susceptibility to the cancer. Such research, however, was limited by the technology of the time, which restricted the investigations to just one candidate gene and only...

That new technology came in the form of genome-wide association (GWA) studies, in which scientists can scour hundreds of thousands of genetic variants that might contribute to various diseases. When this technique was applied to the study of lung cancer, the results were profound: Three independent studies, this month’s Hot Papers, all identified a region on chromosome 15 that was strongly associated with lung cancer risk. Specifically, individuals carrying certain mutations or polymorphisms in this region tended to have higher risk of lung cancer. Not surprisingly, the locus contained three genes that encode three subunits of the nicotinic acetylcholine receptor.

“It makes beautifully plausible sense that something that binds nicotine would have something to do with lung cancer,” recalls Caporaso, who did not participate in those studies. “What could be more logical?” Nicotinic acetylcholine receptors may trigger the behavior that causes lung cancer (smoking) and/or the cancer itself, by interacting with certain tobacco carcinogens to stimulate tumor growth.

Since the publication of these papers, scientists have implicated two additional loci in lung cancer susceptibility, and a new consortium continues to hunt for more. “The idea is we will be doing joint research on lung cancer,” says Rayjean Hung, a cancer epidemiologist at the Samuel Lunenfeld Research Institute in Toronto and the first author of one of the three papers. “It’s going to be a collaborative effort now.”

Cloudy picture

While it seemed clear that chromosome 15 locus was associated with lung cancer, the same region also appeared to be linked to smoking, which exhibits a heredity that’s even stronger than lung cancer, Caporaso says. As a result, it’s unclear whether this region directly increases the risk of lung cancer, increases the risk of smoking—which can lead to cancer—or if there was some kind of interaction between the genetics and the behavior. “We knew that the effect could go to both the addiction and also other carcinogenesis pathways,” says Hung, and the data regarding whether this locus was associated with lung cancer risk directly or indirectly were a bit cloudy.

One of the studies reported an association with lung cancer irrespective of smoking status, while another found an association only in smokers. The third suggested that the effect was mediated by nicotine addiction.

For now, “the question remains unresolved,” Caporaso says. “Nobody is totally convinced [that the effect is independent of smoking]. It’s going to need mechanistic laboratory studies in addition to larger [studies] of nonsmokers.”

Group inhale

Shortly after the publication of this month’s Hot Papers, two follow-up GWA studies implicated two additional loci in lung cancer susceptibility: one on chromosome 51,2 and another on chromosome 6.2 Genes found in these regions include one involved in DNA mismatch repair (a process that has been shown to play a role in lung cancer), and a component of telomerase, the activity of which is believed to be vital for most forms of carcinogenesis.

In addition, several of the authors from these and the three original studies teamed up with NCI researchers, including Caporaso, to conduct a meta-analysis of 11 GWA studies, totaling more than 13,000 cases and nearly 20,000 controls.3 While the massive study did not yield any other gene candidates, it did confirm the association of the chromosome 15 locus across lung cancer tumor types, and narrowed the locus containing the telomerase component to just one type of lung cancer. The telomerase locus also “appears to be associated with lung cancer risk in never smokers,” suggesting that the association is irrespective of smoking, first author molecular epidemiologist Maria Teresa Landi of NCI says in an email.

In an effort to find new genetic factors as well as to better understand those already identified, the International Lung Cancer Consortium (ILCCO) is gathering all available GWAS data, now totaling over 40,000 cases. Such an enormous data set can be used to study specific subgroups in more detail, Caporaso says, such as nonsmokers, women, or different ethnic groups. Members of the consortium meet once a year to discuss what studies can be done using the valuable resource, and recently submitted a joint grant application.

The genetic factors identified so far “explain part of [the variation in lung cancer risk], but not all of it,” says Hung. “We think there might be some other genes associated with lung cancer.

Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson ISI) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.
R. Hung et al., “A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.” Nature, 452:633–37. (Cited 181 times)
R. Thorgeirsson et al., “A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.” Nature, 452:638–41. (Cited 187 times)
C. Amos et al., “Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.” Nat Genet, 40:616–22. (Cited 152 times)
1. J. McKay et al., “Lung cancer susceptibility locus at 5p15.33,” Nat Genet, 40:1404–6.
2. Y. Wang et al., “Common 5p15.33 and 6p21.33 variants influence lung cancer risk,” Nat Genet, 40:1407–9.
3. M. Landi et al., “A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma,” Am J Hum Genet, 85:679–91.

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