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Smoking Gun

April 16, 2010 by Post Team 

Smoking GunSmoking Gun:Scientists have known for years for more than 1 million people die from lung cancer each year smokers. So when it came to seeking a genetic basis for lung cancer, there was much skepticism about the importance of this research, says molecular epidemiologist Neil Caporaso, Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI).

But the evidence that lung cancer tends to run in families suggests there may be a hereditary component of the disease after all, and early studies identified genes that correlated with increased susceptibility to cancer. Such research, however, was limited by the technology of the time, which limits research to a single candidate gene and only a few hundred cases and controls per study. “Although we found some genes [with] the effects weak, this was thought to be unsatisfactory,” Caporaso recalls, “and really seemed to the new technology to help us.”

This new technology came in the form of genome-wide association (GWA) studies in which scientists can search through hundreds of thousands of genetic variants that may 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, which is strongly associated with risk of lung cancer. Specifically, carriers of certain mutations or polymorphisms in this region tended to have higher risk of lung cancer. Not surprisingly, the site contained three genes that encode three subunits of the nicotinic acetylcholine receptor.

“It makes sense that something beautifully that binds nicotine might have something to do with lung cancer,” says Caporaso, who did not participate in these studies. “What could be more logical?” A nicotinic acetylcholine receptors can trigger the behavior that causes lung cancer (smoking) and / or the cancer itself, interacting with certain carcinogens in snuff to stimulate tumor growth.

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

While it seems clear that the locus on chromosome 15 is associated with lung cancer, the same region also appears to be related to smoking, which exhibits a legacy that is even stronger than lung cancer, says Caporaso. As a result, it is unclear whether this region directly increases the risk of lung cancer, smoking increases the risk, which can lead to cancer, or if there was any interaction between genetics and behavior. “We knew that the effect could go both addiction and carcinogenesis pathways other,” says Hung, and data regarding whether this locus is associated with risk of lung cancer, directly or indirectly, were a little cloudy.

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

For now, “the issue remains unresolved,” says Caporaso. “No one is absolutely convinced [that the effect is independent of smoking]. You will need laboratory mechanistic studies, in addition to larger studies [] of non-smokers.”
Inhale Group

Shortly after the publication of work this month, two GWA studies follow two additional loci involved in susceptibility to lung cancer: a 51.2 in the chromosome and one in 6.2 genes on chromosome found in these regions are involved in DNA repair genes (a process that has been shown to play a role in lung cancer), and a component of telomerase, whose activity is believed to be vital for most forms of carcinogenesis.

Furthermore, some of the authors of these and of the three original studies joined with researchers from the NCI, including Caporaso, to carry out a meta-analysis of 11 studies GWA, for a total of more than 13,000 cases and nearly 20,000 controls 3 While the study was massive candidates who do not provide any other gene, it was to confirm the association of chromosome 15 rather than between the pulmonary tumor types of cancer, and reduced the place that contains the component of telomerase for only a lung cancer. Telomerase place also seems to be associated with risk of lung cancer in smokers, suggesting that the association is independent of smoking, the first molecular epidemiologist author Maria Teresa Landi of NCI said 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 collecting all available data GWAS, now totaling more than 40,000 cases. This huge data set can be used to study specific subgroups in more detail, says Caporaso, and non-smokers, women or ethnic groups. The consortium members meet once a year to discuss what studies can be done using the valuable resource, and recently submitted a joint grant application.

Genetic factors identified so far, “explained part of [the change in] the risk of lung cancer, but not everything,” says Hung. “We thought there might be some other genes associated with lung cancer.

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