DNA damage leads to lung cancer

Approximately 85% of lung cancers are caused by tobacco-smoke-acquired carcinogenesis, while worldwide, ~15–25% of lung cancer cases occur in lifetime “never smokers” (less than 100 cigarettes in a lifetime). These etiologic differences are associated with distinct differences in tumor-acquired molecular changes, such as EGFR mutations in never-smoking lung cancers (1,2). Of importance, with cessation of cigarette smoking from public health initiatives, ~50% of all newly diagnosed cases of lung cancer occur in former smokers who ceased smoking >5 years previously. Never-smoking lung cancers represent a distinct disease that occurs more frequently in women and East Asians, targets the distal airways, is usually adenocarcinoma, and frequently has acquired EGFR mutations making it very responsive to EGFR-targeted therapies (1). A multi-step process involving genetic and epigenetic alterations resulting from DNA damage (usually from cigarette smoking) transforms normal lung epithelium into lung cancer and results in “field defects” in histologically normal lung epithelium, as well as a variety of histologic pre-neoplastic/pre-malignant lesions (3,4). The culmination of these changes lead to lung cancers exhibiting all six of the “hallmarks of cancer” (self-sufficiency of growth signals, insensitivity to growth-inhibitory (anti-growth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis; 5). Current information on the molecular steps and their timing in pre-neoplasia, primary cancer, and metastatic disease is the subject of this chapter (6). The identification and characterization of key molecular changes – often involving oncogenes and tumor suppressor genes (TSGs), and importantly, the associated “tumor cell vulnerabilities” that accompany these oncogenotype changes – in the development and progression of lung cancer are of fundamental importance for improving the prevention, early detection, and treatment of this disease. Ultimately these findings need to be translated to the clinic by using molecular alterations, such as biomarkers for early detection, targets for prevention, signatures for personalizing prognosis and therapy selection for each patient, and therapeutic targets to selectively kill or inhibit the growth of lung cancer.