Functional analysis of gastric cancer-specific genes identified by SAGE data and its clinical implication

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The purpose of the study is to identify novel gastric cancer-specific genes through SAGE data analysis and to establish new system of cancer diagnosis oriented towards molecular target therapy. Following results were obtained:1) By comparison between SAGE libraries of gastric cancer (GSE545) and 14 normal organs in combination with RT-PCR, 9 gastric cancer-specific genes (APIN, MIA, MMP-10, DKK4, REGIV, etc.) have been identified.2) By immunostaining, expression of MIA and MMP-10 were correlated with grade of malignancy and poor prognosis. REGIV expression was detected not only in gastric cancer but in colorectal cancer, pancreas cancer and GI carcinoid.3) By ELISA, high levels of REGIV and MMP-10 in sera were detected in 36% and 95% of gastric cancer patients, respectively.4) Through functional analyses, phosphorylation of EGFR and inhibition of caspase-9 were found to participate in apoptosis inhibition by 5-FU. SCP18, whose expression is associated with tumor stage and metastasis, promoted cell invasion by forced expression in gastric cancer cell line.5) Regarding the relation between genetic polymorphism of tumor-related genes and gastric cancer, SNP (G/A) in 5'UTR of the CLDN18, new candidate tumor suppressor of gastric cancer, was found to affect gastric cancer risk (OR-5.17, 95%CI: 2.01-13.3).6) We have developed custom-made oligo-DNA microarray with 207 cDNAs including specific genes identified by SAGE analysis, known genes related to development and progression of cancer, and genes participating in DNA damage response and repair. By examining gene expression profiles of 20 gastric cancers, we identified 23 genes related invasion, nodal metastasis and tumor stage.