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Smoking Has Lasting Effects on Genes

By Cheryl Simon Silver

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Lung Cancer
Microarrays

Some people who smoke respond differently at a genetic level to cigarette smoke than other people who smoke, a new study has found. These people may be at a heightened risk of developing lung cancer because genes that normally protect lung cells against environmental toxins are altered, including some genes linked to cancer.

The researchers profiled the activity of thousands of genes in the lung cells of smokers, non-smokers and former-smokers. They found that smoking alters the activity of many genes in the lung cells that normally form a barrier against environmental toxins.

In particular, in more than ten percent of smokers, the genes that activate enzymes that enable to body to detoxify the smoke fail to work appropriately.

The findings are consistent with what public health officials have long known: that more than 90 percent of people who get lung cancer smoked at some time in their life, and that fewer than fifteen percent of people who smoke heavily will get the disease.

Part of the reason lung cancer is so deadly is that it is exceedingly difficult to diagnose at an early stage. The study raises the possibility that in the future the lung cells of smokers could be tested to see how their genes are behaving.

“Simply by looking at the activity of genes, we could tell if a smoker is not responding appropriately to cigarette smoke,” says Avrum Spira, of Boston University School of Medicine. Smokers who do not produce the enzymes that detoxify smoke might be candidates for more frequent screening for lung abnormalities.

The findings appear online in the Proceedings of the National Academy of Sciences.

The research team, led by Jerome S. Brody of Boston University School of Medicine, will now try to validate the findings in a much larger study. The current study analyzed complete gene profiles of 75 individuals, including 23 people who never smoked, 34 current smokers, and 18 former smokers.

The hope is that down the road the findings will enable researchers to develop early diagnostic tests for lung cancer, the leading cause of cancer deaths in the United States. Researchers from Boston University and Affymetrix Inc., in Santa Clara, California, also contributed to the report.

The study explored a persistent question about the incidence of lung cancer: Why do former smokers, even those who quit smoking decades ago, continue to be more likely to develop lung cancer than individuals who never smoked?

The study showed that two years after smoking stops most genes revert to normal, but thirteen genes, including a number of genes that potentially suppress the growth of tumors, never return to normal levels.

“These permanent changes might explain the persistent risk of lung cancer in former smokers,” the authors write. The risk for people who quit smoking is still lower than that of current smokers.

“We believe there is a genetic predisposition for lung cancer,” Spira says. Still, most people who don’t smoke won’t get the disease.

“To get lung cancer, you likely need a genetic predisposition, and you need to be exposed to the trigger—cigarette smoke,” Spira says.

Spira, A et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Published online in Proceedings of the National Academy of Sciences (June 21, 2004).

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