Smoking increases copy number variations and CIN in lungs in humans and animal models.38, 39 CIN is a marker of poor prognosis for non-small cell lung cancer.40 Inducible Mad2 overexpression CIN model mice, which are defective in the mitotic spindle checkpoint and show CIN, demonstrated a higher rate of recurrence of lung tumor in an experimental setting in which lung tumorigenesis was at first induced through k-ras oncogene addiction then the tumors regressed by the oncogene shutdown.41 This evidence concerns the gene KRAS and cervical squamous intraepithelial neoplasia.