Loss of Heterozygosity and Promoter Methylation, but not Mutation, May Underlie Loss of TFF1 in Gastric Carcinoma

Abstract

SUMMARY:It has been advanced that the trefoil factor (TFF) 1 gene is a candidate tumor-suppressor gene and may be involved in the development and/or progression of human gastric cancer. We aimed to clarify the putative role of TFF1 in gastric carcinogenesis. Ninety gastric carcinomas and eight gastric carcinoma-derived cell lines were screened for TFF1 mutations; subsets of the primary tumors and of the cell lines were subjected to loss of heterozygosity (LOH), immunohistochemistry, and promoter methylation analyses. TFF1 mutations were not detected in any of 90 gastric carcinomas. Eight (28%) of 28 informative cases displayed LOH at the TFF1 locus and absence of TFF1 staining by immunohistochemistry. These results indicate a frequent loss of TFF1 expression in gastric carcinomas through a mutation-independent mechanism. Extensive TFF1 promoter methylation was observed in nonexpressing gastric carcinoma-derived cell lines and tissues. Expressing cell lines, as well as normal gastric mucosa, presented little or no methylation of the promoter. Gastric carcinoma DNA presented de novo methylation of the promoter. These results point to the involvement of promoter methylation in the shutting down of TFF1. We conclude that TFF1 point mutations seem to be a rare event in gastric carcinogenesis. The loss of expression of TFF1 in a proportion of gastric carcinomas may be explained by LOH and methylation of the TFF1 promoter region. Our results further support the role of TFF1 inactivation in gastric carcinogenesis, in agreement with the results obtained in the Tff1-knockout mice model. (Lab Invest 2002, 82:1319 -1326.

Differences in genomic instability between intestinal- and diffuse-type gastric cancer

“…Four of the markers used in the present study (D5S818, CSFIPO, D18S51, D21S11) were located in regions which have been shown to be non-randomly lost during the progression of GCA [26] (Table 2). These chromosomal arms, 5q, 18q, and 21q, have been shown to contain the tumor suppressor genes APC and MCC [33], DCC [34], and trefoil factor 1 [35], respectively. Our tetranucleotide markers reported a rate of LOH of about 20% in the corresponding chromosomal region, consistent with previous reports (Table 2).…”

Expression of Tight-Junction Protein Claudin-7 Is an Early Event in Gastric Tumorigenesis

“…4 -6 We and others have reported that Tff1 expression is remarkably down-regulated in nearly all human gastric cancers. 7,8 Recent reports support the notion that Tff1 may be a candidate tumor suppressor gene that may be involved in development and/or progression of human gastric cancers. 6,7,9 The Tff1 knockout (Ϫ/Ϫ) mouse model was first reported in 1996 as a model for spontaneous development of intestinal-type gastric dysplasia and cancer, similar to human disease.…”

“…7,8 Recent reports support the notion that Tff1 may be a candidate tumor suppressor gene that may be involved in development and/or progression of human gastric cancers. 6,7,9 The Tff1 knockout (Ϫ/Ϫ) mouse model was first reported in 1996 as a model for spontaneous development of intestinal-type gastric dysplasia and cancer, similar to human disease. 10 Thus, the Tff1Ϫ/Ϫ mouse model provides a window to look into molecular alterations that are associated with precancerous lesions and understand the development of gastric cancers.…”

Loss of TFF1 is associated with activation of NF-κB–mediated inflammation and gastric neoplasia in mice and humans

“…TFF1 expression is strongly induced after mucosal injury (6) and is involved in stomach ontogenesis and maintenance of the integrity of the mucosa (2, 3). Molecular studies have shown frequent loss of TFF1 expression in more than two-thirds of gastric carcinomas resulting from a mutation-independent mechanism (7)(8)(9). The silencing of the TFF1 gene in gastric carcinomas is due to loss of heterozygosity (LOH) and methylation of the TFF1 promoter region (7,(10)(11)(12)(13), but mutations are seen only in approximately 5% of gastric carcinomas (7,14).…”