Search for biomarkers of stage II/III gastric cancer and development of individualized therapy.

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4068 Background: Standard therapy for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. Treatment outcomes are expected to be further improved by the development of individualized therapy based on new biomarkers. We have extracted mRNA from frozen specimens of gastric cancer to construct a cDNA bank and searched for new biomarkers of stage II/III gastric cancer. We report currently available results. Methods: The study group comprised 256 patients with stage II/III gastric cancer in whom at least 5 years had passed since surgery (among whom 149 received S-1 as adjuvant chemotherapy). A total of 130 genes were selected on the basis of the results of comprehensive DNA microarray analyses and extraction from serial analysis of gene expression (SAGE) libraries, and other studies. Relative expression levels of each gene in gastric cancer tissue and adjacent normal mucosa were measured by quantitative PCR, and the relations between clinicopathological factors and treatment outcomes were studied. In addition, using 9 types of gastric cancer cell lines, we knocked down the new cancer biomarkers obtained in this study with small interfering RNA (siRNA) and performed functional analysis. Results: In patients with resected stage II/III gastric cancer, INHBA, IGF-1R, CLDN7, and DPD genes were independent prognostic factors. In the subgroup of patients who received S-1-based adjuvant chemotherapy, IGF-1R, INHBA, SULF1, REG4, MMP11, and KIAA1199 genes were independent prognostic factors. Knockdown of the KIAA1199 gene with siRNA markedly inhibited the proliferative and invasive activities of the gastric cancer cell lines and lowered resistance to 5-fluorouracil. Conclusions: Investigatory studies of new biomarkers of gastric cancer identified prognostic factors for patients with resected stage II/III gastric cancer and those who received adjuvant chemotherapy with S-1. At present, the development of small molecule drugs that target KIAA1199 and the joint development of risk stratification tools with the goal of individualized therapy for stage II/III gastric cancer are ongoing.