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Cathepsin E Is a Novel Highly Overexpressed Biomarker in Barrett's Esophagus & Esophageal Adenocarcinoma
Oliver M. Fisher^*1, Angelique Levert-Mignon¹, Sarah J. Lord^2,4, Antony R. Wettstein³, Melissa Thomas¹, Dan Falkenback⁵, Yuri V. Bobryshev¹, Reginald V. Lord^1,4
1Gastro-Oesophageal Cancer Program, St. Vincent's Center For Applied Medical Research, Sydney, NSW, Australia; ²NHMRC Clinical Trials Center, University of Sydney, Sydney, NSW, Australia; ³Diagnostic Endoscopy Center, St. Vincent's Clinic, Sydney, NSW, Australia; ⁴Department of Surgery, Notre Dame University School of Medicine, Sydney, NSW, Australia; ⁵Department of Surgery, University Hospital Lund, Lund, Sweden

Background. The identification of clinically relevant biomarkers for the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC), or of prognosis for patients with EAC, remains an unsolved problem. Cathepsin E (CTSE) is an aspartic proteinase and possible oncofetal antigen that is differentially expressed in the metaplasia-dysplasia-neoplasia sequence of gastric and colon cancer, and is overexpressed in almost all pancreatic ductal adenocarcinomas. Increased CTSE levels are linked to improved survival in lung, bladder and breast cancer. We evaluated CTSE as a biomarker in Barrett's disease including EAC.
Methods. 232 pre-treatment tissues from 166 patients were analyzed (22 normal squamous esophagus (NE) from non-GERD patients, 21 BE IM, 22 BE with dysplasia, 101 EAC). CTSE relative mRNA expression was measured by multiplex tandem RT-PCR, and protein expression by immunohistochemistry.
Results. CTSE mRNA expression levels were more than 1,000-fold higher in BE IM and BE dysplasia tissues compared to NE (p < 0.001; Fig. 1). CTSE levels dropped significantly in EAC tissues but remained significantly higher than NE levels (875 vs. 18.4; p = 0.0048; Fig. 1). A similar expression pattern was present in IHC, with intense staining in IM and dysplasia and less intense EAC staining. In uni- and multivariable analysis CTSE expression was not significantly associated with survival (HR 0.907; 95%CI 0.744 - 1.105, p = 0.33), but CTSE expression above the 25th percentile resulted in a 42% relative risk reduction for death (HR 0.58, 95% CI 0.27 - 1.21, p = 0.15).
Conclusions. Cathepsin E mRNA expression is upregulated more than any known gene in Barrett's IM and dysplasia compared to normal squamous esophagus tissues. Protein expression is similarly highly intense in these tissues whereas mRNA and protein expression levels are reduced in EAC tissues relative to Barrett's precancer tissues. Cathepsin E overexpression may influence survival in some EAC patients. Further studies investigating the biomarker potential and functional role of cathepsin E are warranted.

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