Expression profile of malignant and non-malignant lesions of esophagus and stomach: identification of active expression modules related to inflammation and lipid metabolism
Authors: Luciana I. Gomes, Gustavo Henrique Esteves, Elier B. Cristo, Alex Fiorini Carvalho, Roberto Hirata, Sarah Martins Marques, Helena Brentani, Adriane Pelosof, Cláudia Zitron, Rubens A. Sallum, André Montagnini, Fernando A. Soares, Gilberto Schwartsmann, Eduardo Jordão Neves, Luiz Fernando Lima Reis
Journal: Cancer Research (2005)

3558  A common feature in the pathogenesis of gastric and esophageal adenocarcinoma is chronic inflammation, manifested as gastritis associated to Helicobacter pylori infection and esophagitis. However, not all individuals with these conditions develop cancer, suggesting that other factors are critical in determining whether an individual is at risk for neoplastic progression. One promising approach in experiments of cDNA microarrays exploits the idea that alterations in gene expression might manifest at the level of biological pathways or co-regulated genes sets rather than investigations centered on individual genes. Using cDNA microarrays, we determined the expression profile of 71 samples representing normal stomach mucosa, intestinal metaplasia of the stomach, gastric adenocarcinomas, normal esophagus mucosa, Barrett′s disease and adenocarcinomas of the esophagus. Based on the expression profile of 4600 genes, grouped according to the Kyoto Encyclopedia of Genes and Genomes, we determined functional modules that are differentially active in the various sample groups. The glicerolipid metabolism pathway was very active in intestinal metaplasia tissues and not active in adenocarcinomas. The cytokine-cytokine receptor interaction process was active in intestinal metaplasia and adenocarcinomas tissues and not active in normal mucosa of stomach and esophagus, including esophagitis mucosa. The genes involved in these two processes were selected to perform cluster analysis by K-means algorithm. The best result was obtained with K=4 and, for both processes, we observed a clear separation between squamous tissue samples (normal esophagus mucosa and esophagitis mucosa); tumor samples; and all metaplastic and others columnar samples (normal body and antrum mucosa and normal cardiac mucosa). In a different approach, we used Pearson’s Linear Correlations in order to find par of genes with altered correlation between distinct clinical conditions. The nonparametric test Mann-Whitney was used to determine the statistical significance of the observed differences. Altered expression of IFNAR2, IL4R, CXCL12 and CCL18 was sufficient to discriminate between squamous and columnar tissues. cKIT was a marker for normal gastric mucosa. The expression of IFNAR2 and IL1R2 were augmented in intestinal metaplasia tissues (stomach and esophagus), whereas the expression of CCL25 was augmented only in intestinal metaplasia of stomach. Finally, the expression of TGFB2, CXCL9, IL6, INHBA and INHBB were significantly altered in adenocarcinomas tissues. The role of lipid metabolism and inflammation might be relevant to better understand the process of chronic inflammatory response associated to intestinal metaplasia of the stomach and esophagus and its subsequent progression to adenocarcinoma.