Genetic Associations of Barrett’s Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC), a glandular disease of the esophagus, is a highly lethal form of cancer. According to the Cleveland Clinic, the 5-year survival rate of EAC is less than 20%, and the number of cases has recently been on the rise. To make matters worse, most EAC cases are discovered in late stages of disease when the prognosis is especially poor. This illustrates the dire need for screening tests and ways to detect this insidious cancer early in its progression.

How does EAC arise?

Typically, esophageal adenocarcinoma arises from a sequence of three main events. The first of these is repeated injury of the esophageal epithelium and glands from chronic gastroesophageal reflux disease (GERD). This repeated injury provides a perfect environment for a metaplastic response known as Barrett’s Esophagus (BE) to arise. In this case, metaplasia describes the replacement of normal esophageal epithelium with tissue that is typically found in the intestine in order to better tolerate the repeated acid exposure. Alone, Barrett’s esophagus is not particularly problematic.

However, the danger of Barrett’s lies in its ability to transform into esophageal adenocarcinoma through a progression called the metaplasia-dysplasia-carcinoma sequence. The change in cell type from esophageal to intestinal epithelium, which occurs in BE, is the first step of this sequence. Next, low grade dysplasia develops, in which some cells show signs of precancerous changes. With repeated damage and genetic mutations, the precancerous stage can develop into high-grade dysplasia and finally EAC. 

Since the development of esophageal cancer is a series of genetic mutations involving loss of tumor suppressor genes, researchers have been investigating the associations between particular genes and EAC. In addition, only a small percentage of those with GERD will progress to BE, and a small portion of those with BE will progress to EAC. In order to explain this phenomenon, there has been a search for genes that may cause patients to have an increased risk of progression between these stages of disease. 

Genetic association of CAV3: A recent discovery

Previous studies have indicated that up to 10% of esophageal adenocarcinoma patients have a family history significant for the disease. This suggests that a possible genetic cause may play a role. However, until now, the mechanisms behind inherited predisposition to EAC have been poorly understood. 

A recent discovery by researchers at Case Western Reserve University fills in the gaps in knowledge about inherited EAC risk. In their 2023 article, Garman et al. describe an association between EAC risk and mutations in CAV3, an esophageal submucosal gland gene. 

This study shows a germline mutation in CAV3 in an extended family with prevalent Barrett’s esophagus and resulting esophageal adenocarcinoma. The way this gene relates to esophageal disease progression is by causing defects in the injury repair mechanisms of the esophagus. Normally, caveolins, including caveolin-3, which is encoded by the CAV3 gene, are present in mucosal glands below the surface epithelium of the esophagus. During esophageal injury, including the acid-induced epithelial injury found in GERD, these caveolin proteins rise up to the surface to aid in repair of damaged tissue.

However, the mutation present in the family studied prevents the normal function of caveolin-3. Thus, the ability of the esophagus to repair damage is hindered. Under these conditions, there is a prime environment for the metaplasia-dysplasia-carcinoma sequence to ensue, resulting in a predisposition to EAC development.

Implications for Disease Management

The discovery of this relationship between CAV3 mutations and EAC is groundbreaking in the fields of gastroenterology and GI oncology. This association provides insight into the mechanism of inherited EAC risk and progression, which opens the door for more personalized cancer treatment. Future research will be conducted regarding how repair function can be restored in defective caveolin genes, therefore decreasing cancer risk. Development of therapies targeting the genetic cause of disease also have the potential to extend the lives of EAC patients. 

Even more exciting is the prospect of developing screening strategies for EAC based on genetic testing and family history. If people with increased esophageal adenocarcinoma can be identified early and monitored, there is an opportunity to detect this devastating disease in its early stages when survival rates are much higher. This is especially important in insidious cancers like EAC, which do not typically present with warning signs until late stages, the point at which interventions are no longer curative. 

Summary/Conclusion

Ultimately, a 2023 study done by Case Western Reserve University researchers has provided valuable insight into the mechanism behind a genetic cause of esophageal adenocarcinoma. The results of this research provide opportunities for screening, early detection, and targeted treatment in individuals predisposed to the progression of this deadly disease. Although further research into potential therapies and screening mechanisms is needed, this discovery has laid the foundation for life-saving testing and interventions in EAC patients.