Researchers from Boston University School of Medicine (BUSM) in collaboration¹（合作，勾结） with investigators² at the University of Utah, have discovered a new approach for identifying smokers³ at the highest risk for developing lung cancer. The findings, which appear in the April 7th issue of Science Translational Medicine, will allow the researchers to use a genomic approach to prevent lung cancer in these individuals and to personalize cancer chemoprophylaxis（化学预防，药学预防） and therapy. Cigarette smoke is the dominant⁵ cause of lung cancer in the United States, accounting⁶ for an estimated 90 percent of all cases. While only 10-20 percent of smokers develop lung cancer in their lifetime, there are currently no tools available to identify which of the approximately 90 million current and former smokers in the U.S. are at the highest risk. Unfortunately, diagnosis⁷ is most often made at a very advanced stage where treatment is largely ineffective. The damage caused by cigarette smoke, however, is not limited solely⁸（单独地，唯一地） to the lung, but rather constitutes a 'field of injury' throughout the entire respiratory tract⁹（呼吸道） that is exposed to the toxin¹⁰（毒质，毒素） . Consistent with（与……一致，符合） this idea, study lead author Avrum Spira, MD, MSc, chief of the section of computational biomedicine（生物医学） in the department of medicine at BUSM and his colleagues, previously¹¹ developed a gene¹² expression-based biomarker measured in the cytologically normal bronchial（支气管的） airway¹³ epithelium（上皮，上皮细胞） that reflects an individual's physiologic¹⁴（生理的） response to smoking and distinguishes smokers with and without lung cancer. Although this biomarker is successful at diagnosing lung cancer, it does not identify the signaling pathways underlying¹⁵ these gene expression changes.

Using a novel gene-expression based approach to define oncogenic（致瘤的，瘤原性的） pathway signatures, the researchers, in collaboration with Dr. Andrea Bild at the University of Utah, have now discovered that the expression of genes¹⁶ belonging to one specific cancer-related pathway, PI3K, are activated¹⁷ in the cells that line the airway of smokers with lung cancer. This gene expression activity in the normal cells of the proximal（接近的，临近的） airway precedes（优于，领先） the development of lung cancer and may be reversed（翻转，颠倒） with a specific chemopreventive agent (myo-inositol) that targets this pathway.

"This finding is significant as these cells can be obtained in a relatively¹⁸ non-invasive fashion from the airway of smokers at risk for lung cancer, and does not require invasive sampling of lung tissue where lung tumors normally arise," said Spira, who is also an associate professor medicine and pathology at BUSM.

The BUSM researchers then went on to validate¹⁹（确认，证实） their findings by measuring the biochemical activity of this pathway in the airway epithelial cells from an independent group of smokers with and without lung cancer. "We found that this PI3K pathway gene expression activity is decreased in the airway of high-risk smokers who had regression（逆行，退化） (or improvement) of their premalignant（恶化前的，癌变前的） lesions（损害，机能障碍） following treatment with a potential lung cancer chemopreventive agent known as myo-inositol, and demonstrated that myo-inositol inhibits²⁰ the PI3K pathway in lung cancer cell lines," he added.

According to the researchers, the data suggests that measuring this airway gene expression activity can help determine which specific cancer pathways have been deregulated（解除控制） within an individual smoker⁴, allowing one to tailor a specific drug that will target the pathway to reduce that individual's risk of lung cancer. "This represents a critical advance in the field of lung cancer prevention as there are currently no effective strategies for lung cancer prevention among high risk smokers. Our work has the potential to help address the enormous and growing public health burden associated with lung cancer, the leading cause of cancer-related death among men and women in the US and the world," added Spira.