Biomarkers that predict Barrett’s oesophagus malignant progression

A new paper was just published by my Computational Genomics Group at the Instituto Gulbenkian de Ciência –  CYR61 and TAZ Upregulation and Focal Epithelial to Mesenchymal Transition May Be Early Predictors of Barrett’s Esophagus Malignant Progression. This was a collaborative study with clinicians from the the Lisbon Cancer Centre (Instituto Portugues de Oncologia de Lisboa), funded by a grant of the Harvard Medical School – Portugal program by Fundação para a Ciência e Tecnologia. Barrett’s oesophagus is the major risk factor for oesophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. Barrett’s oesophagus is a fast growing condition associated with bad diets and stress. We used a novel bioinformatics approach to identify genes that could distinguish between a pre-malignant lesion that will progress to an adenocarcinoma, from those, the majority, that do not. These predictions were then tested in a patient series, using methods that are part of the pathology department routine ,and shown to have significant predictive value, i.e. under blind testing, clinicians could state using index samples, which ones would progress. It was very exciting to realize that besides a suggestion for a mechanism for disease progression, one of the putative biomarkers is measurable in blood and urine, opening up the possibility of a non-invasive monitoring approach for Barrett’s oesophagus patients. This work was driven by a former post doc in the group, Joana Cardoso Vaz, who is now Scientific Director of Ophiomics – Precision Medicine.

For those more technically inclined, the full abstract of the paper: “Barrett’s esophagus is the major risk factor for esophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. We sought to identify early biomarkers, predictive of Barrett’s malignant progression, using a meta-analysis approach on gene expression data. This in silico strategy was followed by experimental validation in a cohort of patients with extended follow up from the Instituto Português de Oncologia de Lisboa de Francisco Gentil EPE (Portugal). Bioinformatics and systems biology approaches singled out two candidate predictive markers for Barrett’s progression, CYR61 and TAZ. Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression. Experimental validation by reverse transcriptase quantitative PCR and immunohistochemistry confirmed the up-regulation of both genes in Barrett’s samples associated with high-grade dysplasia/adenocarcinoma. In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett’s esophagus index samples. Finally, we found that CYR61 and TAZ over-expression is correlated with early focal signs of epithelial to mesenchymal transition. Our results highlight both CYR61 and TAZ genes as potential predictive biomarkers for stratification of the risk for development of adenocarcinoma and suggest a potential mechanistic route for Barrett’s oesophagus neoplastic progression.

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