Candidate Oncogenes, ARHGAP4, NOS3, and OR51B5, for the Development of Scirrhous-type Gastric Cancer.

BACKGROUND/AIM: Scirrhous-type gastric cancer (SGC), one of the most intractable cancer subtypes, is characterized by rapid cancer cell proliferation and infiltration accompanied by extensive stromal fibrosis. One of the reasons for its poor prognosis may be the lack of molecular target drugs for SGC, because of the unknown driver genes. Exploration of somatic mutations in the human samples of SGC using next-generation sequencing (NGS) has been hampered by abundant fibrous tissues in these samples. Therefore, this study aimed to determine a novel oncogene by RNA-sequencing using SGC cell lines, avoiding contamination with fibrosis. MATERIALS AND METHODS: In silico analysis of RNA-sequencing public data of the gastric cancer cell line, and RNA- sequencing using five of our unique SGC cell lines, OCUM1, OCUM2MLN, OCUM8, OCUM12, and OCUM14 were performed. RESULTS: We found three differentially expressed genes, ARHGAP4, NOS3, and OR51B5 that are significantly over-expressed in SGC cells. Immunohistochemical analysis indicated that the protein expression levels of these three genes were significantly higher in SGC than in other types of gastric cancer. The prognosis of patients with positive expression of these three genes was significantly poorer than those with negative expression. In particular, ARHGAP4 expression was an independent predictor of poor prognosis and recurrence. CONCLUSION: ARHGAP4, NOS3, and OR51B5 may be candidate driver genes for SGC. ARHGAP4 may be a promising molecular target for SGC.

The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer.

INTRODUCTION: Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC). MATERIALS AND METHODS: We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting. RESULTS: THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor. CONCLUSION: THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.

The Preoperative Geriatric Nutritional Risk Index Predicts Postoperative Complications in Elderly Patients with Gastric Cancer Undergoing Gastrectomy.

BACKGROUND/AIM: The relationship between the preoperative Geriatric Nutritional Risk Index (GNRI) and morbidity of patients with gastric cancer (GC) undergoing gastrectomy has not yet been reported. Our study aimed to investigate whether preoperative GNRI is associated with short-term outcomes in elderly patients with GC. PATIENTS AND METHODS: This study enrolled 348 elderly patients with GC who were more than 75 years old and underwent curative gastrectomy for GC at our Institution between January 2006 and December 2015. GNRI was invoked to stratify patients as high (GNRI≥92; n=190) or low (GNRI<92; n=158) GNRI nutritional status. The clinicopathologic features and short-term outcomes were compared. RESULTS: In multivariate analysis, low GNRI emerged as an independent predictor of postoperative complications (Clavien Dindo classification grade II≤). Low GNRI demonstrated significantly more frequent extra-surgical complications than high GNRI. Significantly more patients with low GNRI suffered from postoperative pneumoniae than patients with high GNRI (p=0.013). On the other hand, the incidence of surgical field complications such as leakage, pancreatic fistula and intraabdominal abscess did not differ significantly between the groups. CONCLUSION: GNRI is useful in predicting postoperative complications of elderly patients with GC undergoing gastrectomy. Preoperative GNRI has merit as a gauge of postoperative complications in the extra-surgical field, especially pneumonia. There was no relationship between preoperative GNRI and surgical field complications in this setting.