Analysis of Gene Expression Identifies Differentially Expressed Genes and Pathways Associated with Lymphatic Dissemination in Patients with Adenocarcinoma of the Esophagus

Abstract

The presence of lymphatic dissemination is an important predictor of survival in esophageal adenocarcinoma (EA). The aim of this study was to discover a prognostic gene expression profile for lymphatic dissemination in EA and to identify genes and pathways that provide oncological insight in lymphatic dissemination. Patients who had lymphatic dissemination (N = 55) were compared with patients without lymphatic dissemination (N = 22). Whole-genome oligonucleotide microarrays were used to evaluate the genetic signature of 77 esophageal cancers. Multiple random validation was used to analyze the stability of the molecular signature and predictive power. Gene set enrichment analysis (GSEA) was applied to elucidate oncogenetic pathways. Lymphatic dissemination was correctly predicted in 75 +/- 14% of lymph node positive patients. The absence of lymphatic dissemination was correctly predicted in 41 +/- 23% of lymph-node-negative patients. Argininosuccinate synthetase (ASS) was selected for validation on the protein level because it was present in most prognostic signatures as well as the list of differentially expressed genes. ASS expression was lower (P = 0.048) in patients with lymphatic dissemination than in patients without. GSEA identified that arginine metabolism pathways and lipid metabolism pathways are related to less chance of developing lymphatic dissemination. The predictive profile does not outperform current clinical practice to predict the presence of lymphatic dissemination in patients with EA. Several genes, including ASS, and genetic pathways which are important in the development of lymphatic dissemination in EA, were identified.