Genetic Variations Increase Lung Cancer Risk for Smokers and Ex-Smokers

Two common inherited genetic variations are associated with increased risk of lung cancer for smokers and former smokers, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reported April 2 in the online edition of Nature Genetics.

"This is the first study to identify a common genetic variant that influences the risk for developing lung cancer," said lead author Chris Amos, phd, professor in M.D. Anderson's department of epidemiology. The variants are present in about half of the Caucasian population studied.

The paper is one of three published by Nature from three unique teams that have identified the same genetic locus as associated with increased lung cancer risk. The findings are a major step forward in identifying those at high risk for non–small-cell lung cancer and for understanding how smoking and genetic factors interact to cause the disease.

Genetic Factors and Molecular Pathways

"The major risk factor for developing lung cancer is cigarette smoking," Dr. Amos said. "What we do not understand is why some long-term smokers develop lung cancer and others don't. There are so many different cancer-causing compounds in tobacco smoke that it's hard to separate them and we don't fully understand the mechanisms that cause lung cancer."

While all smokers and former smokers are at higher risk for lung cancer, less than 20% of these "ever smokers" eventually develop the disease. "We need to get a better handle on how genetic factors increase risk and what molecular pathways are involved in development of lung cancer," Dr. Amos said.

The research team, comprising scientists from M. D. Anderson, Johns Hopkins University, and the Institute for Cancer Research and the University of Cambridge in the United Kingdom, pinpointed two spots of genetic variation on chromosome 15.

The two variants are single-nucleotide polymorphisms (SNPs), places in the human genome that vary by a single DNA chemical building block or nucleotide. Individuals who have ever smoked and who have one or two copies of either of these SNPs have increased risks ranging from 28% to 81% of developing lung cancer, the researchers found.

The team's findings might also provide support for a growing body of evidence suggesting that nicotine, long known as the prime addictive compound in cigarettes, might also play a direct causative role in the development of lung cancer.

There are five genes in the area of chromosome 15 where the two risk-raising SNPs were identified, Dr. Amos explained. Of those, three are nicotine acetylcholine receptor genes that encode proteins that serve as docking sites to which nicotine can bind.

"Once bound, these receptors set in motion a cascade of signals. 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, that will be of great interest," Dr. Amos said.

Another potential causative gene in the area is one that encodes a component of the proteasome, which degrades other proteins. The function of the fifth gene has yet to be identified.

Amos and senior coauthor Margaret Spitz, MD, chair of M.D. Anderson's department of epidemiology, conceived the study, which follows on evidence from epidemiologic research indicating a twofold increase in lung cancer risk for first-degree relatives of lung cancer patients.

To pinpoint genetic variations, the team conducted a series of genome-wide association studies, first genotyping 317,498 different SNPs among 1,154 former and current smokers who developed lung cancer and were seen at M.D. Anderson and 1,137 matched ever-smoker controls in Houston.