Intramucosal Carcinomas of the Stomach: Phenotypic Expression and Loss of Heterozygosity at Microsatellites Linked to the APC Gene

Wu, Libo; Kushima, Ryoji; Borchard, F; Molsberger, G.; Hattori, Takanori

doi:10.1016/s0344-0338(98)80031-9

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…(23,24) Although we found no association between DNA methylation of MGMT and I type GC, MUC2 is a marker of intestinal epithelial cells. Thus, frequent p53 mutations in I type GC (8)(9)(10)(11) may be due to DNA methylation of MGMT.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation profiles of differentiated‐type gastric carcinomas with distinct mucin phenotypes

et al. 2005

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Gastric carcinomas (GC) are classified into four phenotypes according to mucin expression. Previous studies revealed the association of distinct genetic profiles in GC with mucin phenotypic expression; however, the roles of epigenetic changes, such as DNA methylation, are poorly understood. We examined whether the phenotypic expression of GC was associated with DNA methylation of hMLH1, MGMT, p16 INK4a, RAR-beta or CDH1. G astric carcinoma (GC) is one of the most common malignancies worldwide. GC are often classified histologically into two major types: the differentiated and undifferentiated types described by Nakamura et al. Expression of HGM, M-GGMC(1) or the Lauren intestinal and diffuse types (2) based on glandular structure. Various genetic and epigenetic alterations are associated with GC; some are found in both the intestinal and diffuse types, whereas others are type specific.(3,4) It was previously reported that GC can be subdivided according to mucin expression into four phenotypes:(5 -7) (i) gastric or foveolar phenotype (G type); (ii) intestinal phenotype (I type); (iii) intestinal and gastric mixed phenotype (GI type); and (iv) neither gastric nor intestinal phenotype (N type). Despite the usefulness of the Lauren classification, there are several variations of the intestinal-type GC described by Lauren. To better understand the development of GC at the molecular level, it is important to analyze molecular alterations in intestinal-type GC according to the mucin phenotype. Distinct genetic changes appear to be associated with I type and G type GC. p53 mutations and allelic deletions of the adenomatous polyposis coli (APC ) gene are detected more frequently in I type GC than in G type GC, (8)(9)(10)(11) whereas microsatellite instability (MSI) is detected more frequently in G type GC than in I type GC. (10,12) We reported previously that alterations of p73, including loss of heterozygosity and abnormal expression, play important roles in the genesis of G type GC. (13) Several lines of evidence suggest that changes in DNA methylation patterns, such as hypermethylation of CpG islands, are common changes in human cancers.(14) Hypermethylation of CpG islands in promoters is associated with silencing of some tumor-related genes. (15)(16)(17) We previously reported DNA methylation of the hMLH1, (18) MGMT, (19) p16 INK4a , RAR-beta and CDH1 (20) genes. In contrast to the many studies of genetic alterations in G type and I type GC, epigenetic alterations in G type and I type GC are poorly understood. Associations between genetic and epigenetic alterations have been reported. DNA methylation of hMLH1 is associated with MSI, (21,22) and DNA methylation of MGMT is associated with G to A mutations in the K-ras (23) and p53 (24) genes. Because MSI occurs frequently in G type GC, it is possible that DNA methylation of hMLH1 may occur frequently in G type GC. In fact, it has been reported that DNA hypermethylation of hMLH1 occurs frequently in G type GC.(25) Because p53 mutations are detected frequently in I typ...

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Section: Discussionmentioning

confidence: 99%

DNA methylation profiles of differentiated‐type gastric carcinomas with distinct mucin phenotypes

et al. 2005

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“…Mutations of the adenomatous polyposis coli (APC) gene occur during the early stages of gastric adenoma development39 and have been detected in gastric adenomas but not in gastric carcinomas 16. Genetic alteration in microsatellites linked to the APC gene is an extremely early event in stomach carcinomas with intestinal differentiation but a relatively late event in those with gastric differentiation 40. There might be clear differentiation, including genetic status, between group A lesions showing stable differentiation to the intestinal phenotype and groups B and C that mostly differentiate to gastric or mixed gastric and intestinal phenotypes.…”

Section: Discussionmentioning

confidence: 99%

MUC gene expression and histogenesis of adenocarcinoma of the stomach

et al. 2001

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To elucidate the histogenesis of adenocarcinomas of the stomach, we examined MUC gene expression in gland-forming intramucosal neoplastic lesions. Eighty tumors were histopathologically assigned to 1 of the following 3 groups based upon the Vienna classification: group A (low-grade adenoma/ dysplasia), group B (high-grade adenoma/dysplasia) and group C (intramucosal carcinoma). Immunohistochemic staining was performed with monoclonal antibodies against MUC2 (goblet cell mucin), MUC5AC (gastric-foveolar mucin), MUC6 (pyloric-gland mucin) and CD10 (brush border). Ki-67 staining was also carried out. An obvious difference existed in MUC gene expression between lesions in group A and those in groups B and C. The majority of group A lesions strongly expressed intestinal markers in which proliferating cell zones were formed but generally expressed no gastric markers, whereas more than 50% of groups B and C tumors expressed gastric markers. These findings suggest that group A lesions are of a stable intestinal phenotype, whereas those in groups B and C are phenotypically and genotypically unstable, indicating that the adenoma-carcinoma sequence is not a major pathway, but instead that adenocarcinomas arise de novo.

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“…TP53 mutation and allelic deletion of the APC gene are detected more frequently in the intestinal phenotype of GC. (8,16) In contrast, CDH1 gene mutation is detected in differentiated type GC a showing gastric phenotype. (17) Microsatellite instability (MSI) is detected more frequently in the gastric phenotype of GC.…”

Section: Molecular Characterization Of Gastric Cancer Gastric ⁄ Intesmentioning

confidence: 94%

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

et al. 2015

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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 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.

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Intramucosal Carcinomas of the Stomach: Phenotypic Expression and Loss of Heterozygosity at Microsatellites Linked to the APC Gene

Cited by 16 publications

References 35 publications

DNA methylation profiles of differentiated‐type gastric carcinomas with distinct mucin phenotypes

DNA methylation profiles of differentiated‐type gastric carcinomas with distinct mucin phenotypes

MUC gene expression and histogenesis of adenocarcinoma of the stomach

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

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