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Research published in the open-access journal BMC Genomics has revealed that some of the damage caused by smoking cannot be undone and persists long after the smoker has kicked the habit [Chari R et al. BMC Genomics (2007) 8:297]. Permanent changes in the expression of certain genes may explain why around half of newly diagnosed lung cancer patients are former smokers.

Whilst there is no doubt that quitting smoking significantly reduces the risk of illnesses such as heart disease, former smokers continue to have an increased risk of lung cancer and other pulmonary ailments relative to those who have never smoked. In order to investigate the molecular mechanism of this prolonged risk, researchers from British Columbia took bronchial epithelial samples from eight current smokers, twelve former smokers (who had stopped smoking between 1 and 32 years ago) and four individuals who had never smoked. The RNA transcripts in each sample were then evaluated using quantitative serial analysis of gene expression (SAGE) to determine each person’s bronchial gene expression profile, or ‘transcriptome’. Select genes from this investigation were further validated using real-time PCR in a second cohort of nine current, seven former and six never smokers.

Although most human cells contain the full genome comprising nearly 25,000 genes, only a small proportion are active in a specific cell at any given time. When something in the environment changes, certain genes will be switched off whilst others are switched on. These changes, which may include epigenetic alterations to the DNA itself, can be transient or permanent and lead to under or over expression of specific gene products.

By comparing differentially expressed genes between the three groups, researchers were able to identify both reversible and irreversible changes in gene expression as a result of smoking. Amongst the 121 genes only influenced by active smoking are those involved in xenobiotic and nucleotide metabolism, as well as airway mucus secretion. Interestingly, over expression of one particular gene encoding a structural component of mucus has also been implicated in a variety of brain tumours, suggesting a potential role in carcinogenesis. Importantly, the expression of a further 124 genes was irreversibly altered by smoking, including genes involved in the cell cycle and DNA repair, which were under expressed in both current and former smokers. These permanent changes may provide a molecular basis for the persistent lung cancer risk despite smoking cessation.

Comment: This research is an important step towards understanding the adverse effects of smoking at the molecular level. Despite the lack of analysis of differential gene expression between former smokers in relation to the number of years since quitting, the overall message is clear: whilst quitting smoking will significantly reduce your disease risk, not starting in the first place is even better.