Esophageal carcinomas remain a leading cause of cancer-related death worldwide, and the prognosis remains poor with 5-year overall survival of only 17%.1 In the mid-1990s, esophageal adenocarcinoma (EAC) overtook squamous cell carcinoma (ESCC) as the most common esophageal cancer in the United States.2,3 Risk factors include smoking, obesity, and Barrett metaplasia secondary to gastroesophageal reflux, whereas infection with Helicobacter pylori appears to be protective.4
The development of EAC is a multistep process involving numerous genetic changes. According to Hanahan and Weinberg, tumorigenesis involves six hallmark characteristics including self-sufficient growth, insensitivity to antigrowth signals, evasion of apoptosis, sustained angiogenesis, a limitless replicative potential, and tissue invasion and metastasis.5 The genetic changes involved in the metaplasia–dysplasia–adenocarcinoma sequence of EAC will be presented in this review. Whether further characterization of the molecular events leading to EAC will provide new targets for diagnosis, prevention, or treatment remains to be established.
Molecular Events and the Progression to Esophageal Carcinoma
During the progression from dysplastic Barrett esophagus to EAC a number of molecular events have been identified (Fig. 170-1),6 including altered expression of tumor suppressor genes such as p53 and p16, cyclin-dependent kinase inhibitor 2 A (CDKN2 A), and involvement of oncogenes including myc, EGFR, HER2/neu, and c-Met.7–10 Cell cycle markers including polyploidy and aneuploidy also have been identified early in the dysplasia–adenocarcinoma sequence.11–13
Genetic changes involved in the progression from Barrett metaplasia to esophageal adenocarcinoma. Many of the early changes persist as the lesions progress to dysplasia and adenocarcinoma. With permission from Lin J, Beer DG. Molecular biology of upper gastrointestinal malignancies. Semin Oncol. 2004;31(6):476–486.
With the development of high-throughput microarray technologies and concomitant analytic methodologies,14 investigators have sought to identify genes,15,16 proteins, or important regulatory elements such as microRNAs17 or protein kinases18 among which patterns of expression either might distinguish between esophageal dysplasia and carcinoma, or might identify tumors with more likelihood to respond to specific treatment regimens. At the chromosomal level, alterations of gene copy number, such as by gene amplification or deletion, are being characterized in ever-increasing number and detail.19 Such copy-number alterations may be associated with EAC progression and advancing stage.20 Investigators also have catalogued copy-neutral changes, particularly loss of heterozygosity, associated with EAC, using single nuclear polymorphism (SNP) microarrays.21–23 Genome sequencing techniques likely will provide further detailed characterization of gene rearrangements that are important in the pathophysiology of esophageal cancers, as has been demonstrated in a number of solid-tumor malignancies.24
As more studies are published that identify associations between genetic changes and the progression to EAC, it is readily apparent that there is wide variability among such alterations ...