Abstract
Esophageal cancer (EC) is the eighth most common cancer and is the sixth leading cause of death worldwide. The incidence of histologic subtypes of EC, esophageal adenocarcinoma (EAC) and esophageal squamous carcinoma (ESCC), display considerable geographic variation. EAC arises from metaplastic Barrett’s esophagus (BE) in the context of chronic inflammation secondary to exposure to acid and bile. The main risk factors for developing ESCC are cigarette smoking and alcohol consumption. The main somatic genetic abnormalities showed a different genetic landscape in EAC compared to ESCC. EAC is a heterogeneous cancer dominated by copy number alterations, a high mutational burden, co-amplification of receptor tyrosine kinase, frequent TP53 mutations. The cellular origins of BE and EAC are still not understood: animal models supported a cellular origin either from stem cells located in the basal layer of esophageal epithelium or from progenitors present in the cardia region. Many studies support the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. The exact identification of these CSCs, as well as their role in the pathogenesis of EAC and ESCC remain still to be demonstrated. The reviewed studies suggest that current molecular and cellular characterization of EAC and ESCC should serve as background for development of new treatment strategies.
Highlights
Esophageal cancer represents the sixth most common cause of cancer death and the eighth in incidence worldwide
This study showed that Receptor Tyrosine Kinase Receptors (RTK) and their targets are frequently disrupted in esophageal adenocarcinoma (EAC); high-level amplifications are frequently observed for ERR2 (17%), EGFR (11%), MET and FGFR, with a global frequency of RTK amplifications corresponding to 43% [9]
Two recent studies have provided an accurate evaluation of the frequency of malignant progression of Barrett’s esophagus: in a first study, 11,028 patients with Barrett’s esophagus have been analyzed in the time for 5.2 years showing an incidence rate of adenocarcinoma of 12 cases per 1000 per year, which corresponds to a risk of developing EAC 11.3 higher than in the general population [88]; in a second study carried out in Northern Ireland on 8522 patients with Barrett’s esophagus, the combined incidence of EAC, gastric cancer cardia and high-grade dysplasia was 0.22% [89]
Summary
Esophageal cancer represents the sixth most common cause of cancer death and the eighth in incidence worldwide. Developments in high-throughput genomic technologies have led to a better understanding of the disease heterogeneity and of the molecular basis underlying the development of EAC and ESCC [4]. These studies have indicated that ESCC is more similar to other squamous cancers, such as those of head and neck, than to EAC; on the other hand, EAC is more similar to the chromosomally unstable subtype of gastric carcinoma than to ESCC [2,3,4]. The importance of studies of genomic characterization of these tumors is not limited only to a better understanding of disease pathogenesis, and represents a unique and precious tool for the identification of new therapeutic targets. An integrated genomic and cellular characterization at the level of single esophageal cancer, considering the major driver mutations, the tumor heterogeneity and the major biochemical pathways sustaining tumor survival and proliferation, may led to the identification of clinically suitable biomarkers and to drive the development of new multitargeting therapeutic approaches
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