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Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype.

ABSTRACT: Gastric cancer (GC), one of the most common human cancers, can be classified into gastric or intestinal phenotype according to mucin expression. TP53 mutation, allelic deletion of the APC gene and nuclear staining of ?-catenin are frequently detected in the intestinal phenotype of GC, whereas CDH1 gene mutation, microsatellite instability and DNA hypermethylation of MLH1 are common events in the gastric phenotype of GC. Our Serial Analysis of Gene Expression (SAGE) and Escherichia coli ampicillin secretion trap (CAST) analyses revealed that CDH17, REG4, OLFM4, HOXA10, DSC2, TSPAN8 and TM9SF3 are upregulated in GC and that CLDN18 is downregulated in GC. Expression of CDH17, REG4, HOXA10 and DSC2 and downregulation of CLDN18 are observed in the intestinal phenotype of GC. In contrast, OLFM4 is expressed in the gastric phenotype of GC. Expression of TSPAN8, TM9SF3 and HER2 are not associated with either gastric or intestinal phenotypes. Ectopic CDX2 expression plays a key function in the GC intestinal phenotype. MUC2, CDH17, REG4, DSC2 and ABCB1 are direct targets of CDX2. Importantly, these genes encode transmembrane/secretory proteins, indicating that the microenvironment as well as cancer cells are also different between gastric and intestinal phenotypes of GC.

SUBMITTER: Oue N

PROVIDER: S-EPMC4556382 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype.

Oue Naohide N Sentani Kazuhiro K Sakamoto Naoya N Yasui Wataru W

Cancer science 20150707 8

Gastric cancer (GC), one of the most common human cancers, can be classified into gastric or intestinal phenotype according to mucin expression. TP53 mutation, allelic deletion of the APC gene and nuclear staining of β-catenin are frequently detected in the intestinal phenotype of GC, whereas CDH1 gene mutation, microsatellite instability and DNA hypermethylation of MLH1 are common events in the gastric phenotype of GC. Our Serial Analysis of Gene Expression (SAGE) and Escherichia coli ampicilli ...[more]

PMID: 26033320

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Project description:Rationale: Multiple gastric cancer (MGC) is characterized by the presence of more than two different tumors in the stomach. However, the clonal relationship and carcinogenesis of MGC remain unclear. We investigated the clonal relationship and role of germline mutations in the carcinogenesis of MGC. Methods: We gathered 16 multiple gastric cancer patients. Thirty-three tumor samples and sixteen normal gastric tissue or blood samples were obtained from January 2016 to December 2017. We also conducted analyses for 208 gastric cancer and 49 esophagogastric junction cancer (GC-EGJ) tumors from TCGA. DNA extraction from our samples was conducted for whole-exome sequencing (WES). Results: Tumor mutation burden (TMB) was not statistically significant within database and our data in the GC-EGJ (P=0.0591) and GC groups (P=0.3113). The mutation spectrum and signatures also showed uniform distributions in GC and GC-EGJ groups within our data and TCGA database. Among sixteen patients, four were identified as monoclonal, in which 11, 10, 26 and 6 somatic mutations were shared within different tumors of P7, P8, P9 and P16, respectively. However, no common mutation between different tumors of the same patient was found among the other 12 patients. After identifying predisposing genes, we found that germline MSH2 and NCOR2 mutations were significantly dominant in 8/12 and 10/12 of genetic MGC patients. Additionally, all patients were identified with MSH2 mutations in cancer samples of those genetic MGC patients. Taking genetic MGCs as a whole, we identified that TP53 were significantly mutated in 14 of 25 tumor samples. Main conclusions: WES analyses are suggestive of monoclonal and polyclonal origin of MGC, which may promote the classification of MGC into genetic and metastatic MGC. For patients with genetic MGC, germline MSH2 X314_splice variants may contribute to carcinogenesis, thus prompting the consideration of more radical surgery and/or anti-PD-1/PD-L1 therapy.

Project description:BackgroundGastric gland mucin is important for maintaining the basic function of the gastric mucosa, protecting it from foreign substances and reducing the occurrence of gastric diseases. Exploring the phenotype of gastric gland mucus changes during the progression of gastric disease is of great clinical significance.MethodsA total of 483 patients with different gastric diseases were collected in this study, including 82 superficial gastritis (SG), 81 atrophic gastritis (AG), 168 dysplasia (GD), and 152 gastric cancer (GC). Mucin staining was performed using HID-ABpH2.5-PAS method and was further grouped according to the mucin coloration.ResultsThe phenotypic characteristics of mucin during disease progression were divided into neutral, acidic, and mucus-free types. Furthermore, acidic mucus can be divided into type I, type II, and type III. The SG group was dominated by neutral mucus (100%), and the AG was dominated by acid mucus (81.48%), which gradually increased with the severity of atrophy (P < 0.05). The GD and GC groups were dominated by mucus-free (43.45%, 78.29%), and as the degree of GD worsened, neutral and acidic mucus gradually decreased and mucus-free increased (P < 0.001). From the SG, AG, GD, and GC progression, neutral and acidic mucus gradually decreased, and mucus- free gradually increased. Acidic mucin revealed that type III (red-brown black) mucin was predominant in AG, GD, and GC, and increased with the degree of AG, GD, as well as the biological behavior of GC. In the lesion adjacent to high-grade GD or GC, type III acid mucin is predominant.ConclusionThere were three mucin phenotypes in the process of gastric diseases. With the disease progression, the trend of phenotypic change was that neutral and acidic mucus gradually decreased and mucus-free increased. The appearance of type III mucin suggested a relatively serious phase of gastric diseases and may be a more suitable candidate for follow-up monitoring of patients with GC risk.

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Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype.

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Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype.

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