Lung cancer is the leading cause of cancer-related death for both men and women in the United States and the solid tumor with the most defined relationship to a known environmental cause, cigarette smoking. The clinical and biologic aspects of this disease are complex in that four major histologic cancer types, all related to smoking, can arise from the bronchial epithelium, including large cell undifferentiated, squamous cell, adeno-, and small cell lung carcinomas. The first three types, collectively known as non-small cell lung cancer (NSCLC), metastasize later than the small cell tumors (SCLC) and some cases can be cured by early surgery. SCLC is one of the most highly metastatic tumors in humans and has less than a 5 percent 5-year survival rate.
There are no well-defined syndromes for inherited lung cancer. However, several genes confer genetic predisposition for development of lung cancer. These genes include the nicotinic acetylcholine receptor genes CHRNA3, CHRNA5 and CHRNB4, as well as several genes involved in the metabolism of carcinogens.
Extensive studies have identified chromosomal regions commonly deleted or amplified in lung cancer, as well as specific genes commonly mutated or inactivated by DNA hypermethylation. Integrated analyses of these data have identified numerous genes that are commonly involved in the development of lung cancer; these genes include KRAS, the MYC family, EGFR, ERBB2, ALK, NKX2-1, TP53, CDKN2A/p16, RB1 and LKB1. Recent studies also implicate several microRNAs in lung cancer.
There are excellent animal models for lung cancer. These models include both carcinogen induced and genetically modified models, in which the effects of specific genes and carcinogens in lung cancer can be explored, and targeted therapeutic strategies can be developed.
Many of the genes implicated in lung cancer are associated with significant prognostic and therapeutic implications, and some, particularly EGFR and ALK, are already important therapeutic targets. We are on the edge of an exciting era in lung cancer therapy, in which knowledge of specific genetic lesions will dictate effective personalized therapy.