Genetic Alterations in Esophageal Cancer

In the United States, esophageal cancers are of the squamous cell type (ESCC) or adenocarcinoma (EADC). Other esophageal malignant neoplasms are rare. Smoking and alcohol, particularly consumption of hard liquor, are strongly associated with development of ESCC in the United States and Europe. Dietary factors such as vitamin deficiencies, trace-metal deficiencies, fungal contamination of food, and high nitrite and nitrosamine content are contributing factors in China and Africa. Other predisposing influences include gastrointestinal disorders such as achalasia, Plummer-Vinson syndrome, longstanding celiac disease, and tylosis. Males and African Americans are more likely to develop ESCC in the United States, whereas EADC is more common in males and Caucasians. The incidence of EADC has increased markedly in the past two decades, both in the United States and abroad. In many countries, the incidence of EADC is increasing at a rate that exceeds that of any other malignancy. It is well accepted that esophageal adenocarcinomas arise from Barrett’s esophagus, a premalignant condition of the esophagus. The risk of EADC appears to be at least 30 times greater in those with Barrett’s esophagus than in those without. Barrett’s esophagus represents conversion of the normal squamous epithelium to a columnar intestinal metaplasia, in response (in part) to chronic injury from chronic gastroesophageal reflux. Similarly to other types of gastrointestinal cancers, an accumulation of genetic alterations follows the dysplasia-adenocarcinoma sequence in esophageal adenocarcinoma. Although certain genetic alterations appear more often or earlier than others, it does not appear that there is a uniform sequence of mutations leading from normal esophageal mucosa to invasive esophageal adenocarcinoma, although some mutations tend to occur early and others late.