Over the past decades, it has become recognized that cancer is a genetic disease. Therefore, the biology of lung and esophageal cancer must be considered from the perspective of genetic changes in the epithelial cells of these organs. In this chapter, we will highlight many of these known individual genetic changes as well as groups of genetic changes.
Oncogenes are genes that lead to increased proliferative capacity of cells. Because they are activating mutations, mutation or overexpression of only one of two normal proto-oncogenes per cell is required for transformation. Oncogenes may lead to increased proliferation through a variety of mechanisms, including augmented growth rate, increased mitotic rate, and decreased rate of apoptosis.
Ras is perhaps the best-known oncogene. The Ras family of proteins consists of three members, HRas, NRas, and KRas, the last of which is implicated in 30% to 40% of human lung adenocarcinoma.1 Wild-type Ras is a membrane-associated G protein that serves as a link between tyrosine kinase receptors at the membrane and cytoplasmic second messenger molecules. These second messenger molecules participate in a proliferative signaling cascade that activates mitogen-activated protein kinase (MAPK) resulting in increased proliferation. This proliferation is caused by mutations in KRas codons 12, 13, and 61, all of which ablate KRas' GTPase activity and constitutively activate KRas.
In both individual studies and a meta-analysis, the presence of mutated KRas in resected lung cancer portends a poor prognosis.2-4 Although the presence of these mutations may identify aggressive tumors, a portion of the prognostic impact may be explained by poor response to adjuvant chemotherapy. In the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) North American intergroup study, the JBR.10 trial, the subgroup of patients with Ras mutations did not experience a survival advantage.5 Because localization of Ras to the membrane is dependent upon farnesylation, farnesyltransferase inhibitors may be more effective in patients with Ras mutation.
In addition to mutation of Ras, control of normal Ras protein levels may be important in lung cancer tumorigenesis. Recently, Ras was found to be an important target of the let-7 microRNA family. MicroRNAs are 22 nucleotide RNA molecules that negatively regulate gene expression by silencing messenger RNAs or by targeting microRNAs for destruction. Lung tumors exhibit lower levels of let-7 than normal lung,6 and low expression levels of let-7 have been demonstrated as predictive of poor survival.7-9
Interestingly, oncogenic Ras mutations occur almost exclusively in adenocarcinomas of smokers.10,11 This may relate to the effect of benzo-alpha-pyrenes on the bronchial epithelium.12 Perhaps smoking cessation efforts will eventually lead to fewer Ras-positive tumors in the future.
In esophageal cancer, Ras mutations have also been reported in patients with high-grade dysplasia and adenocarcinoma.9 These mutations are rarely found in Barrett metaplasia.
Epidermal Growth Factor Receptor (EGFR)