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Inactivation ofp16INK4ain the Rb pathway is among the most common somatic alterations observed in nonsmall cell lung cancers (NSCLCs). While epigenetic inactivation of thep16INK4agene promoter has been shown to be associated with increased tobacco carcinogen exposure, little investigation of any similar association of homozygous deletion or mutation ofp16INK4aand tobacco use has been completed. In 177 consecutive NSCLCs, we examined the determinants ofp16INK4ahomozygous deletion and mutation, including the pattern of tobacco smoking and asbestos exposure. We observed thatp16INK4ahomozygous deletion occurred at a higher frequency in never smokers as compared to former and current smokers (p= 0.01). This observation suggested that tumors from these patients might be more prone to DNA deletion events; consistent with this, epigenetic silencing of the DNA double-strand break repair genesFancFandBRCA1was also associated with homozygous deletion ofp16INK4a(p= 0.002 andp= 0.06, respectively). Finally, mutation ofp16INK4awas rare and only occurred in patients who were smokers. Hence, the character of somatic alteration in the Rb pathway (deletion, mutation or methylation silencing) in NSCLC is associated with the pattern of tobacco exposure, suggesting that susceptibility to lung cancer is, at least in part, mediated by the biological mechanism that selects for the character of the induced somatic lesion.