The major cause of lung cancer is tobacco use, particularly cigarette smoking. Lung cancer cells may have ≥10 acquired genetic lesions, most commonly point mutations in ras oncogenes; amplification, rearrangement, or transcriptional activation of myc family oncogenes; overexpression of bcl-2, Her2/neu, and telomerase; and deletions involving chromosomes 1p, 1q, 3p12-13, 3p14 (FHIT gene region), 3p21, 3p24-25, 3q, 5q, 9p (p16 and p15 cyclin-dependent kinase inhibitors), 11p13, 11p15, 13q14 (rb gene), 16q, and 17p13 (p53 gene). Loss of 3p and 9p is the earliest event, detectable even in hyperplastic bronchial epithelium; p53 abnormalities and ras point mutations are usually found only in invasive cancers. A small but significant subset of pts with adenocarcinoma have activating mutations in the gene for the epidermal growth factor (EGF) receptor, or activating fusion events involving the alk or ros gene. Driver mutations in lung cancer are depicted in Fig. 69-1.