Genome Study Implicates Human Chromosome 15 in Genetic Susceptibility to Lung Cancer

The Bottom Line

• Results of a genome-wide association study (GWAS) indicate that a specific region of human chromosome 15 is associated with lung cancer risk.
• This region contains two genes that produce different components of proteins known as neuronal nicotinic acetylcholine receptors, which are found on nerve cells and are stimulated by the chemicals acetylcholine and nicotine.
• The results also indicated that the influence of this chromosomal region on lung cancer risk is independent of the effects of smoking on lung cancer risk.

The Whole Story

Tobacco smoke causes most cases of lung cancer worldwide, and smoking is by far the most important risk factor for this disease. According to a U.S. Surgeon General's report, cigarette smoking accounts for approximately 90 percent of all lung cancer deaths among men in this country and almost 80 percent of lung cancer deaths among women. In addition, tobacco smoke has been linked to other cancers, including cancers of the bladder, oral cavity, pharynx, larynx (voice box), esophagus, cervix, kidney, pancreas, and stomach, as well as acute myeloid leukemia.

Nonetheless, research has indicated that genetic factors also play a role in lung cancer development. Epidemiologic studies have consistently shown that first-degree relatives of lung cancer patients have a two- to three-fold increased risk of lung cancer compared with relatives of control subjects, regardless of the smoking history of the relatives. In addition, individuals with inherited mutations in certain genes have an increased risk of lung cancer.

To identify common DNA variations, or single-nucleotide polymorphisms (SNPs), that are associated with lung cancer risk, researchers at the University of Texas M.D. Anderson Cancer Center in Houston, the Johns Hopkins University School of Medicine in Baltimore, and the Institute of Cancer Research and the University of Cambridge in the United Kingdom conducted a GWAS in which the genomes of 1,154 ever (current or former) smokers with non-small cell lung cancer and 1,137 ever-smoker control subjects were compared. SNPs are changes in the DNA code that are found in many people, usually in at least one percent or more of the individuals in a population. In contrast, mutations are changes in the DNA code that are rare and may be unique to an individual or their hereditary line. Another way of thinking about SNPs is that they are mutations that have persisted and become common in a population. The DNA changes in mutations and SNPs can be beneficial, harmful, or have no obvious effect.

The genome comparisons led to the identification of 10 SNPs that seemed to be associated with lung cancer risk. The researchers examined these SNPs further in analyses that involved additional lung cancer patients and control subjects. In the end, they found that two SNPS located in a specific region of chromosome 15 were significantly associated with lung cancer risk. Smokers who had one copy (that is, inherited from a single parent) of either SNP had about a 30 percent increased risk of lung cancer, and those with two copies (that is, inherited from both parents) of either SNP had about an 80 percent increased risk of lung cancer. The researchers also found that the effect of DNA variation in this region of chromosome 15 on lung cancer risk appears to be independent of the effects of smoking on lung cancer risk.

The identified region of chromosome 15 contains three known genes, and there is evidence that two of them, CHRNA3 and CHRNA5, might be associated with lung cancer development and progression. These genes produce different components of proteins called neuronal nicotinic acetylcholine receptors, which are found on nerve cells and are stimulated by the chemicals acetylcholine and nicotine.

At the time this research study was published, nearly identical results were reported by another research team. The results of these two studies provide the strongest evidence to date that commonly found genetic variations can increase susceptibility to lung cancer.

Publications:
Amos CI, Wu X, Broderick P, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genetics 2008;40(5):616-622.
Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008; 452(7187):633-637.