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Lymph node metastasis is one of the most important determinants of patient outcome in esophageal cancer patients. Expressional profiling may reveal gene sets that can be used as molecular markers of progression from absence of lymph node metastases to its presence. Aim: To identify changes in gene expression that may indicate a potential to develop lymph node metastases in selected patients who had undergone similar surgical treatment. Methods: Expressional profiling was performed using CodeLink oligonucleotide array, in 9 paired samples of normal esophageal epithelium, lymph node-positive (N1) and lymph node-negative (N0) squamous cell carcinomas (SCC) of the esophagus. Each set of differentially expressed genes was defined based on the independent pair-wise comparison of tumor samples with normal tissues, or tumor samples of lymph node-positive (N1) and the lymph node-negative (N0) groups with each other. We also compared patterns of gene expression in N0 and N1 SCCs to detect genes which are differentially expressed in N1 relative to N0 carcinomas. Results: 429 genes were differentially expressed in N0 tumors relative to normal tissues. 273 genes were differentially expressed in N1 tumors relative to normal tissues. 117 genes are differentially expressed in both N0 and N1 tumors relative to normal tissues. These genes might be used for detection of the early stages of malignant transformation if they progressively increase/decrease expression in the line of normal tissues/N0/N1 tumors. Only 9 genes were up-regulated in both group of tumors. Other common genes were down-regulated. 72 genes were differentially expressed in the N1 SCC relative to N0 SCC of esophagus. To check this hypothesis we used unsupervised two-dimensional hierarchical clustering using these 72 genes as potential classifier of expressional signature. Unsupervised clustering exploiting 72-gene signature could separate samples, belonging to the N0 tumors from samples belonging to the N1 tumors. Four major clusters were discovered in the result of this approach. First is presented by genes down-regulated in N0 but up-regulated in N1 (27 genes). Second cluster is presented by genes down-regulated or not changed in N0 but drastically up-regulated in N1 (4 genes). Third cluster is presented by genes down-regulated in N0 but not changed in N1 (6 genes), and fourth cluster is presented by genes up-regulated or not changed in N0 but down regulated in N1 (35 genes).

Conclusions: 1. Suppression of some specific functional genes is associated with malignant transformation ; 2. The genes selected in this investigation have a high potential as a novel diagnosis markers for esophageal SCC; 3. Microarray expressional analysis of genes may permit to discriminate tumors more prone to develop lymph node metastases.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA