A subset of gastric carcinomas shows histologic evidence of a multistep process, progressing from gastric adenoma to gastric carcinoma. We examined gene expression changes during the gastric adenoma-carcinoma sequence in 26 snap-frozen samples (normal mucosa, adenoma, and carcinoma samples from eight patients and two additional carcinomas) by oligonucleotide microarray. Unsupervised hierarchical clustering analysis demonstrated differential gene expression between gastric normal mucosa, adenomas and carcinomas. We identified 319 and 422 genes differentially regulated in adenoma and carcinoma, respectively, relative to normal mucosa, using a combination of Welch's t-test and fold-change analysis. Applying a combination of robust multi-category support vector machines to the data, reveal that 39 and 21 genes were gradually up- and down-regulated, respectively, in succession in normal mucosa, adenoma, and carcinoma samples. We validated gene expression levels of four genes: hydroxyprostaglandin dehydrogenase 15 (HPGD), follistatin-like 1, trefoil factor 1 (TTF1) and trefoil factor 2 (TFF2) by RT-PCR and found direct correlation with microarray results. The expressions of the TFF2 and HPGD genes were further evaluated by immunohistochemistry in 103 adenomas and 70 carcinomas; expression of both proteins was decreased in these tissues. The progressive alteration in gene expression in the transition from normal mucosa to carcinoma suggests that these changes may play critical roles in gastric carcinogenesis.
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