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Smoking is by far the number one risk factor for lung cancer, but why do some pack-a-day smokers get the disease while others don't? The answer may depend in part on whether they inherited a specific genetic variation, according to a new study published this week in Nature Genetics.

Researchers from 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, pronounced "snips") on chromosome 15 associated with an increased likelihood of developing lung cancer.

While this study identified a subset of smokers who are at an increased risk for lung cancer, all smokers are at risk. Lung cancer is the leading cause of cancer death in both men and women in the United States. In 2008, there will be an estimated 161,840 deaths from lung cancer (90,810 among men and 71,030 among women). More people die of lung cancer than of colon, breast, and prostate cancers combined. And smoking is responsible for about 87% of lung cancer deaths. These variants explain just 18% of the risk associated with lung cancer, according to Dr. Amos

The research team analyzed more than 300,000 SNPs in 8,709 Caucasians in Texas and the United Kingdom, many of whom were current or former smokers. After conducting a series of genome-wide association studies (GWAS), scientists identified 2 SNPs that were strongly associated with lung cancer. 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 whether they were heavy or light smokers and whether they smoked for many years or just a few.

SNPs are small changes within a gene; for a variation to be considered an SNP, it must occur in at least 1% of the population.About half of the study population had 1 or 2 variants of the SNPs identified by the researchers. The 2 SNPs the researchers identified were very close together and tended to be similar in individuals. For example, if a person had a variant at 1 SNP, the same variant likely showed up in the nearby SNP. Similarly, when a person had 2 variants at a SNP they almost always had 2 variants at the nearby SNP.

Researchers found these SNPs in a region of chromosome 15 that has 5 genes, 3 of which have been identified as nicotine-receptor genes, a discovery that raises the possibility that nicotine might somehow involved in the start and growth of cancer, according to Amos.

However, it’s not yet clear if nicotine has a role in causing these cancers. "There is as yet no convincing evidence that nicotine itself contributes importantly to carcinogenesis, but this is an active area of research. The prevailing view is the carcinogenicity of tobacco comes predominantly from constituents other than nicotine, not from nicotine," said Michael Thun, MD, American Cancer Society, vice president, epidemiology and surveillance research. "The actual mechanism by which these variants work will have to be determined in future studies."

Tobacco smoke is comprised of more than 4,000 chemicals, at least 60 of which are known to cause cancer. However, scientists aren't sure exactly how the specific compounds work to cause lung cancer.

"We need to get a better handle on how genetic factors increase risk and what molecular pathways are involved in the development of lung cancer," said Amos.

The research was funded by the National Cancer Institute and is built on an ongoing study of lung cancer patients at MD Anderson. Researchers plan expand the study to include African Americans, as well as people who have never smoked.

Two other studies that came out this week in Nature 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.

It's too early to know how this research might be applied, but some suggest doctors may be to use this information to better tailor cessation regimens and better target individuals who should be screened for lung cancer. For more information on these topics, see the American Cancer Society's Guide to Quitting Smoking and "What's So Bad About Tobacco?"

Citation: "Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1." Published in the April 2 online edition of Nature Genetics. First author: Christopher I. Amos, PhD, The University of Texas M.D. Anderson Cancer Center.