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Smoking Alters Gene Activity in Lungs and Tumors

The strong link between smoking and lung cancer has long been clear, but the underlying genetic and molecular changes have been harder to pin down. Now NIH scientists have shown that cigarette smoking distinctively alters gene activity and that these changes can persist for years, contributing to cancer long after a person has kicked the habit.

Lung cancer is the leading cause of cancer death worldwide, and 90% of lung cancers are caused by smoking. Scientists had previously shown that smoking-related tumor cells have overly active, or overexpressed, genes that regulate cell division. But the roles of these and other genes in early tumor development and cancer deaths have been uncertain.

A team of researchers based largely ar Â鶹´«Ã½'s National Cancer Institute (NCI) set out to clarify how smoking alters gene expression and leads to cancer. They used microarray technologies, or gene chips, to analyze the activities of thousands of genes simultaneously in lung tissue samples. The samples included both normal and tumor tissues collected from 74 patients who had lung adenocarcinoma, the most common type of lung cancer. Participants included current and former smokers, as well as people who had never smoked.

As reported in the February 20, 2008, issue of the journal PLoS ONE, the researchers identified 135 genes that were expressed differently in the tumors of current smokers than in the lung tumors of people who had never smoked. Smokers had significantly increased activity in genes that regulate the cell cycle and cell division. Former smokers had just slightly altered activity in some of these same genes. In a few cases, these genetic changes persisted even 2 decades after the participants had quit smoking.

When they compared non-tumor lung tissues, the researchers found that current smokers had altered activity in nearly 100 genes. Many of these genes play a role in regulating immune response. The researchers speculate that these genes might be working to protect lung tissues from the onslaught of toxic chemicals in cigarette smoke. These immune-response genes were not significantly altered in former smokers, suggesting that non-tumor lung tissue can recover from the effects of previous smoking.

The scientists also looked at how smoking-related genetic changes relate to survival in lung cancer patients. They found that the risk of lung cancer death increased 3-fold in smokers who had altered expression of 2 specific cell-cycle-related genes in non-tumor lung tissue.

“More studies are needed to confirm that the gene expression changes are due to smoking and affect tumor development or progression," said Dr. Maria Teresa Landi, a researcher in NCI's Division of Cancer Epidemiology and Genetics and first author of the report. "If confirmed, these genes could become important targets for preventing and treating lung cancer in smokers."