Preferential Loss of Fhit Expression in Signet-Ring Cell and Krukenberg Subtypes of Gastric Cancer

Chang, Yu-Ting; Wu, Ming–Shiang; Chang, Chee‐Jen; Huang, Pei‐Hsin; Hsu, Su-Ming; Lin, Jaw–Town

doi:10.1097/01.lab.0000028060.37763.d5

Cited by 10 publications

(6 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our approach using 24 genes led us to identify specific genes (BRCA1, p73, RARb, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) associated with a particular variant of gastric cancer, the signet-ring cell type. It has been suggested that signet-ring cell type is epidemiologically, clinico-pathologic, and molecularly a distinct subtype of gastric cancer (47,48). Thus, our finding not only identified the methylation profile of this emerging variant of gastric cancer but also gives support to the hypothesis that the hypermethylation of the CpG island does not occur randomly but by specific selection process targeting key tumor suppressor genes (41).…”

Section: Discussionsupporting

confidence: 72%

Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer

Bernal¹,

Aguayo

Villarroel

et al. 2008

Clinical Cancer Research

106

View full text Add to dashboard Cite

Purpose: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary. Experimental Design: To search for these biomarkers, we evaluated the DNA methylation patterns of 24 genes by Methylation-specific PCR in primary tissues from 32 retrospectively collected gastric cancer cases (testing group). Correlation between methylation and gene expression was evaluated in the MKN-45 cell line after treatment with 5-aza-2 ¶-deoxycytidine. The most frequently hypermethylated genes were next evaluated in primary tissues and plasma samples from 43 prospectively collected gastric cancer cases as well as plasma samples from 31 asymptomatic age-and gender-matched controls (validation group). Results: In the testing group, 11 genes were hypermethylated in at least 50% of cases (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, 3OST2, p14, p15, DAPK , and p16). Eight genes (BRCA1, p73, RARb, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) were statistically associated with a particular variant of gastric cancer, the signet-ring cell type (P = 0.03). Seven genes (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, and 3OST2) were next evaluated in the validation group. We confirm the high frequency of methylation in primary tumors for all seven genes. However, only APC and Reprimo were frequently methylated in pair plasma samples. In asymptomatic controls, only Reprimo was infrequently methylated in comparison with plasma from gastric cancer cases (P < 0.001). Conclusion:Our results identified specific methylation profile associated to signet-ring cell-type histology and aberrant hypermethylation of Reprimo as a potential biomarker for early detection of gastric cancer.

show abstract

Section: Discussionsupporting

confidence: 72%

Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer

Bernal¹,

Aguayo

Villarroel

et al. 2008

Clinical Cancer Research

106

View full text Add to dashboard Cite

show abstract

“…In a study by Chang et al a preferential loss of FHIT expression was observed in signet-ring cell cancers, an observation which is in line with the loss of FHIT expression in our group of diffuse type gastric cancers (Chang et al 2002). In a study by Chang et al a preferential loss of FHIT expression was observed in signet-ring cell cancers, an observation which is in line with the loss of FHIT expression in our group of diffuse type gastric cancers (Chang et al 2002).…”

Section: Discussionsupporting

confidence: 86%

“…The FHIT gene deletions have been reported in a variety of human malignancies (Ohta et al 1996;Marchetti et al 1998;Tanimoto et al 2000;Wistuba et al 2002) and several studies have suggested that the subsequent absence or reduction in FHIT protein may play a key role in gastric carcinogenesis (Tamura et al 1997;Gemma et al 1997;Baffa et al 1998;Lee et al 2001a;Chang et al 2002). However, little is known about the association of FHIT alterations with clinicopathological parameters and the prognostic role of FHIT in gastric carcinoma is still debated (Noguchi et \al.…”

Section: Introductionmentioning

confidence: 99%

Loss of FHIT protein expression correlates with disease progression and poor differentiation in gastric cancer

Rocco

Schandl

Chen

et al. 2003

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

Purpose: The fragile histidine triad (FHIT) gene has recently been proposed as being a tumor suppressor gene. FHIT gene deletions or aberrant transcripts have been identified in a variety of human malignancies, including gastric carcinomas, suggesting that FHIT may play a key role in tumor development. However, the clinical impact of FHIT mutations in gastric carcinogenesis is still debated. Our purpose was to investigate whether FHIT expression in human primary gastric carcinoma is associated with the histological type, grade or stage of the tumor. Methods: We analyzed a well-characterized set of 137 primary gastric cancers. FHIT protein expression was evaluated in gastric mucosal samples, both from the tumor and tumor-free areas by immunohistochemistry. Furthermore, in a subgroup of 30 patients, FHIT mRNA expression was assessed by nested RT-PCR. Results: Absent or reduced expression of FHIT protein correlated significantly with diffuse type (P<0.0001), poor differentiation (P<0.0001), and advanced stage (P<0.0001) of gastric cancer. In contrast, FHIT protein was strongly expressed and uniformly distributed in tumor-free areas. The FHIT mRNA expression was absent or altered in diffuse and poorly differentiated carcinomas. Conclusion: These results show that the expression of FHIT in gastric carcinoma is related to the type, grade, and stage of the tumor. We suggest that FHIT expression may be considered a potential prognostic factor in gastric cancer.

show abstract

“…The loss of FHIT is often a genetic alteration identified in Krukenberg tumors . An aberrant transcript from this gene has been found in stomach cancer .…”

Section: Discussionmentioning

confidence: 99%

GAGE12 mediates human gastric carcinoma growth and metastasis

Lee

Song

Chae

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

The spontaneous metastasis from human gastric carcinoma (GC) remains poorly reproduced in animal models. Here, we established an experimental mouse model in which GC progressively developed in the orthotopic stomach wall and metastasized to multiple organs; the tumors colonized in the ovary exhibited typical characteristics of Krukenberg tumor. The expression of mesenchymal markers was low in primary tumors and high in those in intravasating and extravasating veins. However, the expression of epithelial markers did not differ, indicating that the acquisition of mesenchymal markers without a concordant loss of typical epithelial markers was associated with metastasis. We identified 35 differentially expressed genes (DEGs) in GC cells metastasized to ovary, among which overexpression of GAGE12 family genes, the top-ranked DEGs, were validated. In addition, knockdown of the GAGE12 gene family affected transcription of many of the aforementioned 35 DEGs and inhibited trans-well migration, tumor sphere formation in vitro and tumor growth in vivo. In accordance, GAGE12 overexpression augmented migration, tumor sphere formation and sustained in vivo tumor growth. Taken together, the GAGE12 gene family promotes GC growth and metastasis by modulating the expression of GC metastasis-related genes.Gastric carcinoma (GC) slowly metastasizes to the lymph nodes, liver, peritoneum, and ovary. 1,2 Poor prognostic features associated with gastrointestinal (GI) tumors in the ovary characterize GC metastasis to the ovary, referred to as Krukenberg tumor. Krukenberg tumor is established via blood or lymphatic vessels and displays abundant mucinfilled signet ring cells and diffuse sarcomatoid proliferation of ovarian stroma. 3-8 Despite the high incidence, an orthotopic mouse model that can recapitulate the GC or Krukenberg tumor pathobiology has not been established. In addition, genes involved in GC metastasis have not been systematically investigated in an appropriate model, necessitating the development of animal models that represent the process of secondary organ metastasis in human GC. Primary tumors invade into neighboring blood vessels, usually, by undergoing a loss of epithelial and gain of mesenchymal characteristics (epithelial-mesenchymal transition, EMT), which drives the motility and early behavior of invasive carcinomas. 9 In contrast, in the metastasized organs, a gain of epithelial and loss of mesenchymal characteristics (mesenchymal-epithelial transition, MET) can occur, and is likely correlated with the extravasation or colonization of cancer cells.Although, the expression of GAGE genes is limited to germ cells in healthy individuals, members of the GAGE gene family are anti-apoptotic proteins that modulate apoptotic regulators. Therefore, it has been suggested to have potential roles in cancer, 10,11 and is, in fact deregulated in a wide range of cancers. 12,13 GAGE gene expression correlates with poor prognosis in gastric cancer, esophageal carcinoma, and neuroblastoma. 14-16 However, little is known about thei...

show abstract

Preferential Loss of Fhit Expression in Signet-Ring Cell and Krukenberg Subtypes of Gastric Cancer

Cited by 10 publications

References 28 publications

Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer

Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer

Loss of FHIT protein expression correlates with disease progression and poor differentiation in gastric cancer

GAGE12 mediates human gastric carcinoma growth and metastasis

Contact Info

Product

Resources

About