| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | COVER ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
||||||||
|
||||||||||
| ||||||||||||||||||||||||||||||||||||||||
NEWS & VIEWS |
|
Researchers from The University of Texas MD Anderson Cancer Center, Johns Hopkins University, the University of Cambridge, and the UK-based Institute for Cancer Research have pinpointed 2 single-nucleotide polymorphisms (SNPs) on chromosome 15 associated with an increased likelihood of developing lung cancer, a major step in understanding the molecular interactions that lead to the disease.
"We have found the signposts along the genome that indicate increased risk for lung cancer, but we still don't know which gene is being affected," said lead author Chris Amos, PhD, professor, MD Anderson Department of Epidemiology.
The research team conducted a series of genome-wide association studies to look for common genotype variations that might be associated with lung cancer. They first analyzed 315,450 SNPs in 1,154 current and former smokers who had lung cancer and a control group of 1,137 ever-smokers who did not get the disease, matching cases with controls according to smoking behavior, age, and number of years since cessation. Participants were recruited from Houston, Texas.
Ten of the most significant genetic associations the researchers found were then replicated in 2 additional case-control datasets: one from the same group in Texas (711 cases and 632 controls) and the other from a population in the United Kingdom (2,012 cases and 3,062 controls). In both replications, the researchers saw an increased risk (P <1 x 10–17) associated with 2 specific SNPs, rs10151730 and rs8034191, both mapping to an 88-kb region on chromosome 15.
All of the participants in this study were White and of European descent. About half of the study population had 1 or 2 variants of the SNP identified by the researchers. The 2 SNPs identified were very close together and tended to be similar in individuals. For example, if a person had a variant at one SNP, the same variant likely showed up at the nearby SNP. Similarly, when a person had 2 variants at a SNP, they almost always had 2 variants at the nearby SNP. Individuals who smoked and had 1 or 2 of these specific SNPs were at a 28% to 81% increased risk of developing lung cancer, an indicator that held regardless of degree of dependence and number of years smoked.
While this study identifies a subset of smokers who are at an increased risk for lung cancer because of their genotype, all smokers are at risk and not just for lung cancer. Smoking is a leading risk factor for cardiovascular disease, stroke, pulmonary disease, and other cancers.
"Even if a smoker knew his genetic profile wasn't associated with an increased risk for lung cancer, that doesn't mean he can just smoke with impunity," said Michael Thun, MD, Vice President, Epidemiology and Surveillance Research, American Cancer Society. "More smokers die from heart disease and stroke than lung cancer."
The larger question this study raises is how these inherited factors might predispose an individual to addiction, according to Thun. "These genetic variants may well be mediated by mechanisms that influence dependence. If we could better understand the biology of addiction, we could better tailor treatment," he said.
Amos and his colleagues found these SNPs in a region of chromosome 15 that has 5 genes, 3 of which have been identified as nicotinic acetylcholine receptor genes, but it is not yet clear what role nicotine or its derivatives might play in causing lung cancer. The fourth gene encodes a component of proteasome, which degrades proteins, and might be a causative gene. Researchers have not yet identified a function for the fifth gene. "Nicotine is known to activate cell proliferation, new blood vessel development, and growth factors while upregulating several signaling pathways. If these are indeed causal genes, they will be of great interest," Amos said.
According to Thun, there is as yet no convincing evidence that nicotine itself contributes importantly to carcinogenesis. "This is an active area of research," he said. "The prevailing view is the carcinogenicity of tobacco comes predominantly from constituents other than nicotine, not from nicotine. The actual mechanism by which these variants work will have to be determined in future studies."
The research, published online April 2, 2008, in Nature Genetics (doi:10.1038/ng.109), is built on an ongoing 17-year study of lung cancer patients at MD Anderson Cancer Center. Researchers plan to expand the study to include African Americans, as well as people who have never smoked.
Two other studies, published concomitantly in Nature (2008;452:633–637 and 638–642), found similar associations on chromosome 15. One study looked at SNPs and lung cancer risk among smokers from 6 European regions, the other at a population in Iceland. The latter study looked at the issue of dependence; the others were focused solely on finding the lung cancer association.
It is too early to know how this research might be applied in practice, but Amos says he hopes one day clinicians will be able to use this information and additional genetic data to better target individuals who should be screened for lung cancer and possibly help gauge an individual's risk for other smoking-related cancers. SNPs in this region could also be further studied to see if they can predict how individuals undergoing smoking cessation will respond to existing therapies according to their genotypes. According to Amos, the more immediate use for these findings may be in developing smoking intervention therapies that are better targeted to individual needs.
| ||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | COVER ARCHIVE | SEARCH | TABLE OF CONTENTS |
