Smoking plays a role in lung cancer development and now scientists have shown that smoking also affects the way genes are expressed, leading to alterations in cell division and regulation of immune response. Notably, some of the changes in gene expression persisted in people who had quit smoking many years earlier.

To investigate the effects of smoking on gene activity in lung tissue, the researchers examined the gene expression profiles -- patterns of gene activity -- in early-stage lung tumors and non-tumor lung tissue of smokers, former smokers, and people who had never smoked cigarettes. Gene expression was measured in 58 fresh-frozen tumor and 49 fresh-frozen non-tumor samples from 74 participants of the Environment And Genetics in Lung cancer Etiology (EAGLE) study, a large lung cancer study that was conducted in the Lombardy region of Italy. Adenocarcinoma tumor samples were evaluated in this study because adenocarcinoma is the most common type of lung cancer, and it occurs in both smokers and people with no history of smoking. The participants were 44 to 79 years of age, and 28 were current smokers, 26 were former smokers, and 20 had never smoked. The researchers also obtained detailed medical information about the participants (for example, whether individuals had previous lung diseases or chemotherapy) and biochemically confirmed participants' smoking status.

Using microarray techniques, which allow researchers to look at the activity of thousands of genes simultaneously, they identified 135 genes that were differently expressed in tumors of smokers vs. people who had never smoked. Among these genes, 81 showed decreased expression and 54 showed increased expression in tumor tissue.

Most of the genes showing significantly increased expression, e.g., TTK, NEK2, and PRC1, are involved in cell cycle regulation and mitosis. The cell cycle is a step-wise sequence of events in which a cell grows and ultimately divides to produce two progeny, or daughter, cells. During the cell cycle, the chromosomes of the parent cell are duplicated and then, in a step called mitosis, divided equally between the daughter cells, ensuring that each daughter cell inherits a complete set of chromosomes. The cell apparatus responsible for the proper division of chromosomes is called the mitotic spindle.

The researchers also found similar expression of many genes among current smokers and former smokers in tumor tissue. Several of these genes, such as STOM, SSX2IP, and APLP2, remained altered in participants who had quit smoking more than 20 years before the study. Therefore, smoking seems to cause long-lasting changes in gene expression, which can contribute to lung cancer development long after cessation.

Looking at non-tumor lung tissues, the team found decreased activity for 73 genes and increased activity for 25 genes in current smokers. The genes most affected by smoking play a role in immune response-related processes, possibly as a lung defense mechanism against the acute toxic effects of smoking. However, non-tumor tissues seem to be able to recover from the effects of smoking. The researchers did not identify significant changes in the immune response-related genes in former smokers.

To gain a better understanding of the impact of smoking-related changes in gene expression on lung cancer survival, the researchers compared the overall gene expression smoking profile in lung tumor and non-tumor tissues with survival. They found that the altered expression of the cell cycle-related genes NEK2 and TTK in non-tumor tissues was associated with a three-fold increased risk of lung cancer mortality in smokers. 

About 90 percent of lung cancer deaths among men and almost 80 percent of lung cancer deaths among women can be attributed to smoking. In 2006, approximately 20.8 percent of U.S. adults were cigarette smokers. Cigarette smoking remains the leading preventable cause of death in the United States, causing an estimated 438,000 deaths, or about one out of every five deaths each year.