Frequent Epigenetic Silencing of thep16Gene in Non-small Cell Lung Cancers of Tobacco Smokers

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Abstract
Epidemiological studies have demonstrated a causal link between tobacco smoking and lung cancer. We investigated the association between inactivation of the p16 gene and tobacco smoking in 51 non‐small cell lung cancers (NSCLCs). Aberrations of the p16 gene were studied by PCR single‐strand conformation polymorphism analysis, followed by direct sequencing, microsatellite analysis, methylation‐specific PCR, and immunohistochemistry. Mutations were detected in 3.9% (2/51) of the tumors; the tumors carrying mutations were from smokers. The incidences of loss of heterozygosity, homozygous deletion, and promoter methylation in 37 smokers vs. 14 non‐smokers were; 45.9% vs. 28.6%, 16.2% vs. 7.1%, and 35.1% vs. 7.1%, respectively. Among these, only the association between promoter methylation and tobacco smoking was statistically significant (Pp16 silencing by tobacco smoking. Loss of p16 protein expression was apparent in 49% (25/51) of the tumors, and was associated with tobacco smoking (PPp16 gene mainly through the epigenetic mechanism, ultimately increasing the risk of NSCLC, especially the squamous cell histological type.