Molecular biology of Barrett's adenocarcinoma

Abstract

Objective: To review the current knowledge on the genetic alterations involved in the development and progression of Barrett's esophagus-associated neoplastic lesions.

Summary background data: Barrett's esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE predisposes patients to the development of esophageal adenocarcinoma. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable, but most of the adenocarcinomas are detected at an advanced stage. Despite advances in multimodal therapy, the prognosis for invasive esophageal adenocarcinoma is poor. A better understanding of the molecular evolution of the Barrett's metaplasia to dysplasia to adenocarcinoma sequence may allow improved diagnosis, therapy, and prognosis.

Methods: The authors reviewed data from the published literature to address what is known about the molecular changes thought to be important in the pathogenesis of BE-associated neoplastic lesions.

Results: The progression of Barrett's metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. Some of the molecular alterations already showed promise as markers for early cancer detection or prognostication. Among these, alterations in the p53 and p16 genes and cell cycle abnormalities or aneuploidy appear to be the most important and well-characterized molecular changes. However, the exact sequence of events is not known, and probably multiple molecular pathways interact and are involved in the progression of BE to adenocarcinoma.

Conclusions: Further research into the molecular biology of BE-associated adenocarcinoma will enhance our understanding of the genetic events critical for the initiation and progression of Barrett's adenocarcinoma, leading to more effective surveillance and treatment.

Figure 1. The cell cycle. Mitosis (M phase) is the process of nuclear division. Replication of DNA occurs in the S (synthesis) phase. The interval between M phase and S phase is called the G1 (gap) phase, and the interval between the end of the S phase and the beginning of the M phase is the G2 phase. Cells can exit the cell cycle and enter the G0 phase, which is the quiescent state.

Figure 2. p53 and cell cycle regulation. With DNA damage there is upregulation of wild-type p53 protein. This leads to increased transcription of p53-regulated genes (e.g., p21, bax-1, bcl-2), which inhibit the cell cycle. This facilitates DNA repair, or the cell enters the apoptotic pathway. In this way p53 provides genomic stability. Mutations in the p53 gene render the p53 protein inactive, and the damaged DNA is transmitted.

Figure 3. Signal transduction from the cell membrane to the nucleus and the proteins (only protooncogene products) involved. Activation (e.g., mutations) of the genes encoding growth factors, their receptors, or the signal transduction pathway genes (ras, src, myc, bcl-2) can lead to constitutive activation of the cell cycle. EGF, epidermal growth factor; TGF, transforming growth factor.

Figure 4. Genes involved in cell cycle progression and inhibition. Cell cycle progression from G1 into S phase requires activation of the cyclin-dependent kinases (CDK4/6) in association with cyclin D1. This active complex phosphorylates the retinoblastoma protein (Rb). Phosphorylated Rb releases Rb-bound transcription factors (E2F family). Free E2Fs transactivate genes that are essential for entry into the S phase and DNA replication. At the G1 checkpoint, there are also negative regulatory signals controlling the cell cycle, namely inhibitors (p16, p21, and p27) of activated cyclin–CDK complexes.

Figure 5. Genetic alterations involved in the progression of Barrett’s metaplasia toward Barrett’s adenocarcinoma. Alterations that occur in the early stages are usually also present in the advanced histologic stages. In each histologic category, the alterations are placed randomly; there is no hierarchical order.