Abstract
The current high mortality rate of esophageal adenocarcinoma (EAC) reflects frequent presentation at an advanced stage. Recent efforts utilizing fluorescent peptides have identified overexpressed cell surface targets for endoscopic detection of early stage Barrett's-derived EAC. Unfortunately, 30% of EAC patients present with gastroesophageal junction adenocarcinomas (GEJAC) and lack premalignant Barrett's metaplasia, limiting this early detection strategy. We compared mRNA profiles from 52 EACs (tubular EAC; tEAC) collected above the gastroesophageal junction with 70 GEJACs, 8 normal esophageal and 5 normal gastric mucosa samples. We also analyzed our previously published whole-exome sequencing data in a large cohort of these tumors. Principal component analysis, hierarchical clustering and survival-based analyses demonstrated that GEJAC and tEAC were highly similar, with only modest differences in expression and mutation profiles. The combined expression cohort allowed identification of 49 genes coding cell surface targets overexpressed in both GEJAC and tEAC. We confirmed that three of these candidates (CDH11, ICAM1 and CLDN3) were overexpressed in tumors when compared to normal esophagus, normal gastric and non-dysplastic Barrett's, and localized to the surface of tumor cells. Molecular profiling of tEAC and GEJAC tumors indicated extensive similarity and related molecular processes. Identified genes that encode cell surface proteins overexpressed in both Barrett's-derived EAC and those that arise without Barrett's metaplasia will allow simultaneous detection strategies.
Highlights
Over 17,000 new cases of esophageal cancer will be diagnosed in the US in 2015, of which 61.5% will be esophageal adenocarcinomas (EAC) [1]
We found that 77% (54/70) of gastroesophageal junction adenocarcinomas (GEJAC) arose in the absence of Barrett’s esophagus (BE), significantly more frequent (p=3.13e-05) than among esophageal adenocarcinoma originating within the tubular esophagus (tEAC) samples (46%; 24/52)
Given the strength of this result, the consistency with previous studies [8, 10, 17, 20], and difficulties associated with clear demarcations on the basis of anatomical site of origin in advanced tumors, we chose to compare the 54 GEJACs without evidence of underlying BE to the 28 EACs with histologically confirmed BE
Summary
Over 17,000 new cases of esophageal cancer will be diagnosed in the US in 2015, of which 61.5% will be esophageal adenocarcinomas (EAC) [1]. Over the past three decades the incidence of EAC in the US has risen at a rate of 7.5% per year [2], with other Western countries reporting similar increases [3, 4]. This disease presents within a characteristic demographic, such that approximately 80% of new cases arise within Caucasian males over the age of 40 years [5, 6], and while the reasons for the rapid incidence increase are undetermined, it is clear that obesity, smoking and chronic gastroesophageal reflux each play an important role. There is a pressing need to implement efficient, accurate surveillance programs among high-risk populations
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