Genetic Variant Greatly Increases Lung Cancer Risk for Light, Non-Smokers

Genetic Variant Greatly Increases Lung Cancer Risk for Light, Non-Smokers

March 2010

NIH researchers and collaborators on a major, genetic epidemiology study of lung cancer, have identified a genetic variant that greatly increases the risk of disease for individuals who inherit it, even if they have never smoked or are light smokers. The finding suggests that any level of tobacco exposure increases susceptibility for lung cancer in this group, underscoring the dangers from any type of cigarette smoke exposure. The study is published in the March 9, 2010 early online issue of the journal Cancer Research.

"Smoking is a poison for everybody," said co-author Joan Bailey-Wilson, Ph.D., a National Human Genome Research Institute (NHGRI) statistical geneticist and co-chief of NHGRI's Inherited Disease Research Branch. "For these folks, just a small amount of smoking puts them at high risk for lung cancer."

Each year, more than 1 million people worldwide die from lung cancer, including more than 150,000 in the United States. Smoking is by far the greatest risk factor for lung cancer and is associated with more than 75 percent of lung cancer deaths. The authors of the study point out the added importance of smoking prevention and early cancer detection procedures for individuals with a family history of lung cancer.

The analysis is part of a larger research initiative known as the Genetic Epidemiology of Lung Cancer Consortium (GELCC), a family study of lung cancer that has been ongoing for more than 10 years. The NHGRI and the National Cancer Institute (NCI) are among 12 participating research institutions and universities across the country engaged in the research.

The researchers followed up on clues from the study of 93 families who have had at least two incidences of lung cancer among relatives. Among those 1,500 individuals, nearly 500 were affected with lung cancer. In a 2004 study conducted by GELCC, the researchers identified a large region on human chromosome 6 that conferred a greater lung cancer risk in a subset of families with many affected individuals. In April 2009, the group identified a gene, RGS17, that is located in this region on chromosome 6, and that is associated with an increased susceptibility to lung cancer in family members with a history of the disease. Work is ongoing to determine if variants in the RGS17 gene account for increased lung cancer risk in the GELCC families that are linked to chromosome 6q.

The goal of the present study was to further characterize this previously noted signature of genetic susceptibility on chromosome 6q. This signature for lung cancer susceptibility was within a longer stretch of DNA than the RGS17 gene itself — a portion of chromosome 6q called a haplotype, containing multiple genes that tend to be inherited together.

To organize their data, the researchers divided smoking exposures into four categories: those whose smoking habit could be characterized as never, light, moderate or heavy.

For family members without the genetic lung cancer risk haplotype, the risk of developing the disease tracked closely with the level of smoking. As would be expected, heavy smokers take on a significantly greater risk of developing lung cancer than moderate smokers, who are at a significantly greater risk than light smokers.

But in family members with the genetic risk haplotype, even light smoking resulted in a greatly increased risk for developing lung cancer, "about 3-fold higher than in light smokers with unknown carrier status or non-carrier status," said Dr. Bailey-Wilson. This result stands out further because the risk of developing lung cancer in light smokers who carried the risk haplotype was very similar to the risk in moderate and heavy smokers who carry the susceptibility variant. However, in smokers, the risk of lung cancer was higher in carriers of the risk haplotype than in non-carriers for all levels of exposure. This suggests that any degree of smoking exposure confers high risk of lung cancer in family members with the risk haplotype.

"The findings are really intriguing and are consistent with everything else we have seen in past studies looking for major risk alleles for lung cancer," said Dr. Bailey-Wilson, explaining that the work is an ongoing effort. "More studies will need to be done to further define the risks and to explain the linkage signal in this region. If we determine exactly which gene is involved and how it works to increase cancer risk, it may help us target people who have extremely high risk from second-hand smoke and it may help us understand how lung carcinogenesis occurs. This might allow for better treatments and for targeted smoking cessation efforts."

Currently, there is no publically available genetic screening for the genetic variant on 6q responsible for this lung cancer susceptibility effect. Regarding advice to the public, Dr. Bailey-Wilson notes, "Anyone who smokes has a high risk of lung cancer, as well as increased risk for other diseases. Our best advice is to not smoke and to avoid exposure to passive tobacco smoke."

For more information about lung cancer, go to Lung Cancer [cancer.gov].

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