Up-regulation of CLDN1 in gastric cancer is correlated with reduced survival

Background: The genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified. There are also remarkable geographical differences in the distribution of this disease. Our aim was to identify the most differentially regulated genes in 20 gastric adenocarcinomas from a Norwegian selection, compared to matched normal mucosa, and we have related our findings to prognosis, survival and chronic Helicobacter pylori infection. Methods: Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 20 patients immediately following surgical resection of the tumor. Whole genome, cDNA microarray analysis was performed on the RNA isolated from the sample pairs to compare the gene expression profiles between the tumor against matched mucosa. The samples were microscopically examined to classify gastritis. The presence of H. pylori was examined using microscopy and immunohistochemistry. Results: 130 genes showed differential regulation above a predefined cut-off level. Interleukin-8 (IL-8) and Claudin-1 (CLDN1) were the most consistently up-regulated genes in the tumors. Very high CLDN1 expression in the tumor was identified as an independent and significant predictor gene of reduced post-operative survival. There were distinctly different expression profiles between the tumor group and the control mucosa group, and the histological subsets of mixed type, diffuse type and intestinal type cancer demonstrated further sub-clustering. Up-regulated genes were mapped to cell-adhesion, collagen-related processes and angiogenesis, whereas normal intestinal functions such as digestion and excretion were associated with down-regulated genes. We relate the current findings to our previous study on the gene response of gastric epithelial cells to H. pylori infection. Conclusions: CLDN1 was highly up-regulated in gastric cancer, and CLDN1 expression was independently associated with a poor post-operative prognosis, and may have important prognostic value. IL-8 and CLDN1 may represent central links between the gene response seen in acute H. pylori infection of gastric epithelial cells, and ultimately gastric cancer

Improved Survival after Implementation of Multidisciplinary Team Meetings, Perioperative Chemotherapy, Extended Lymphnode Dissection and Laparoscopic Surgery in the Treatment of Advances Gastric Cancer

Aims: The treatment of gastric cancer has changed in the western countries during the last decade. This includes multidisciplinary team (MDT) meetings, perioperative chemotherapy, extended lymph node dissection, and laparoscopic surgery, all of which were gradually implemented at our department from 2008. The aim of the present study was to determine the effect of these changes on morbidity and survival. Material and Methods: 185 patients with gastric cancer were operated with curative intent from 2000 until 2016 in this retrospective, observational, follow-up study; 83 before implementation of modern principles in 2008 (period 1) and 102 were treated after 2008 (period 2). Results: The resection rate (94% vs 92.8%) and mortality rates (4.8% vs 2.9%) did not differ between the two periods. In period 2, 48 patients (47.1%), received neoadjuvant chemotherapy. In 36 patients (35.3%), laparoscopic surgery with D2 lymphadenectomy was performed. There was a significantly higher yield in the number of lymph nodes in period 2 compared to period 1 (14 vs 8, p < 0.001). This is also apparent between laparoscopic and open surgery in the second period (32 vs 10, p < 0.001). The five-year survival rate was significantly improved after the change in treatment principles with an estimated improvement from 30% to 40% between the periods (p = 0.033). Conclusion: The combined effect of MDT meetings, neoadjuvant chemotherapy, extended lymphnode dissection and laparoscopy has improved the prognosis of gastric cancer patients. KEYWORDS Gastric Cancer, Chemotherapy, Laparoscopy, Survival, D2 Lymphadenectom

GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer

International audienceBackgroundA large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival.MethodsBiopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material.ResultsMost of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression.ConclusionsThe different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance