PHG Foundation | Early changes in gene expression may predict lung cancer risk

Early changes in gene expression may predict lung cancer risk
19 April 2010 | By Dr Susmita Chowdhury | Research article

Overall tobacco smoking is estimated to be responsible for approximately 29% of all cancer deaths and up to 90% of lung cancer deaths in the UK (see Cancer Research UK). However, despite the fact that smoking is a very strong risk factor for lung cancer, the majority of smokers never develop this specific disease; genetic factors (along with other environmental factors) are presumed to be involved in overall susceptibility. On the basis of the concept that genomic changes in airway epithelial cells reflect damage due to smoking, US researchers have developed a genomic approach for identifying smokers at the highest risk of developing lung cancer [Gustafson AM et al. Sci Transl Med. 2010 Apr 7;2(26):26ra25].


In order to explore the patterns of pathway deregulation, the investigators examined oncogenic pathways in apparently normal epithelial cells from the upper bronchial airway by looking at gene expression patterns in 60 current and former smokers with lung cancer and 69 current and former smokers without lung cancer. They found that genes involved in the phosphatidylinositol 3-kinase (P13K) signaling pathway were significantly up-regulated in lung cancer patients relative to patients without lung cancer (although there was no evidence for a copy number change in the P13K gene itself). The gene expression findings were further validated using biochemical tests on airway epithelium of a cohort of smokers with clinical suspicion of lung cancer, and a significantly higher P13K activity was found in smokers who were ultimately diagnosed with cancer. Similarly, increased P13K pathway activation was observed in normal airways of smokers with pre-cancerous lesions. Since activation of the pathway occurred in normal airway epithelium distal to the location of the tumour, the authors concluded that the PI3K pathway was altered early in lung cancer development.

The researchers also found that P13K pathway gene expression activity was decreased in the airway of high-risk smokers (those with pre-cancerous lesions at risk of progression to lung cancer) following treatment with the chemopreventative agent myo-inositol. This agent also inhibited the P13K pathway in vitro. They concluded that deregulation of the P13K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer, and that genomic profiling of these relatively accessible airway cells (which may be sampled using a non-invasive procedure such as bronchoscopy) could provide early warning of cancer development and allow intervention to prevent it.

Comment: Previous research has revealed the potential value of gene expression profiling for precise diagnosis and prognosis in forms of cancer, and this is an area of extensive research (see previous news). This study provides an interesting demonstration of how genomic data might also prove valuable in prediction and prevention of another major cancer type. Whether the specific agent used will be effective in preventing cancer is another question that must await further results.

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PHG Foundation | Early changes in gene expression may predict lung cancer risk
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