Dataset Information

Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas.

ABSTRACT: Tissue inhibitor of metalloproteinase 3 (TIMP-3) promoter methylation has been linked to loss of TIMP-3 expression in various cancers. In this study, we analyzed TIMP-3 gene methylation using MethyLight assay and TIMP-3 mRNA expression using reverse transcription-polymerase chain reaction analysis in 22 esophageal cancers, 27 gastric carcinomas, and 7 cancer cell lines. We also analyzed TIMP-3 protein expression by immunohistochemistry and its association with clinicopathological characteristics in two cohorts of gastric cancer comprising a total of 347 patients. The TIMP-3 gene was more commonly methylated in adenocarcinomas of the esophagus (9/13) and stomach (9/15) than in the corresponding nonneoplastic mucosa of the esophagus (1/8; P = .024) and stomach (2/14; P = .021). In gastric cancer patients, TIMP-3 was decreased in a diffuse-type gastric cancer and in cancers with poor differentiation and was associated with poor survival (P = .04). In summary, we observed frequent TIMP-3 promoter methylation in adenocarcinomas of the esophagus and stomach and the loss of TIMP-3 expression seems to be of clinical and prognostic relevance in these cancers.

SUBMITTER: Gu P

PROVIDER: S-EPMC2386541 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas.

Gu Ping P Xing Xiangbin X Tänzer Marc M Röcken Christoph C Weichert Wilko W Ivanauskas Audrius A Pross Matthias M Peitz Ulrich U Malfertheiner Peter P Schmid Roland M RM Ebert Matthias P A MP

Neoplasia (New York, N.Y.) 20080601 6

Tissue inhibitor of metalloproteinase 3 (TIMP-3) promoter methylation has been linked to loss of TIMP-3 expression in various cancers. In this study, we analyzed TIMP-3 gene methylation using MethyLight assay and TIMP-3 mRNA expression using reverse transcription-polymerase chain reaction analysis in 22 esophageal cancers, 27 gastric carcinomas, and 7 cancer cell lines. We also analyzed TIMP-3 protein expression by immunohistochemistry and its association with clinicopathological characteristics ...[more]

PMID: 18516293

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Project description:The incidence of esophageal and junctional adenocarcinoma has increased 6 fold in the last 30 years and 5 year survival remains less than 14%. Most patients present with advanced disease and current staging is limited in its ability to predict survival. We aimed to generate and validate a molecular prognostic signature for esophageal adenocarcinoma. Gene expression profiling was performed and the resulting signatures correlated with clinical features for 91 snap frozen esophageal and junctional resection specimens. Gene expression profiles were obtained from 76/91 of the samples (82%). 119 genes were significantly associated with survival and 270 genes with the number of involved lymph nodes. Three genes were prognostic at the protein level in the external validation dataset. This three gene signature outperformed all the pathological features at predicting survival in this independent cohort (p<0.001). Total RNA isolated from human tissue sections was used to make fluorescently labeled cRNA that was hybridized to DNA oligonucleotide. Briefly, 4 µg of total RNA was used to synthesize dsDNA through reverse transcription. cRNA was produced by in vitro transcription and labeled postsynthetically with Cy3 or Cy5. Two populations of labeled cRNA, a reference population and an experimental population, were compared with each other by competitive hybridization to microarrays. Two hybridizations were done with each cRNA sample pair using a fluorescent dye reversal strategy. Human microarrays contained oligonucleotide probes corresponding to approximately 21,000 genes. All oligonucleotide probes on the microarrays were synthesized in situ with inkjet technology (Agilent Technologies, Palo Alto, CA). After hybridization, arrays were scanned and fluorescence intensities for each probe were recorded. Ratios of transcript abundance (experimental to control) were obtained following normalization and correction of the array intensity data. Gene expression data analysis was done with the Rosetta Resolver gene expression analysis software (version 7.0, Rosetta Biosoftware, Seattle, WA).

Project description:Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear beta-catenin expression, pointing to activated T-cell factor (TCF)/beta-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear beta-catenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/beta-catenin activation is caused by mutations in either adenomatous polyposis coli (APC), beta-catenin exon 3, AXIN1, AXIN2 or beta-transducin repeat-containing protein (beta-TrCP). In GEJ adenocarcinomas, very few APC and beta-catenin mutations have been found. Therefore, the mechanism of Wnt pathway activation remains unclear. In the present study, we did not find AXIN1 gene mutations in 17 GEJ tumours with nuclear beta-catenin expression (without beta-catenin exon 3 mutations). Six intragenic single nucleotide polymorphisms (SNPs) were identified. One of these, the AXIN1 gene T1942C SNP, has a frequency of 21% but is only very recently described despite numerous AXIN1 gene mutational studies. We provide evidence why this SNP was missed in single strand conformation polymorphism analyses. The AXIN1 gene G2063A variation was previously described as a gene mutation but we demonstrate that this is a polymorphism. With these six SNPs loss of heterozygosity (LOH) was found in 11 of 15 (73%) informative tumours. To investigate a possible AXIN1 gene dosage effect in GEJ tumours expressing nuclear beta-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear beta-catenin. LOH was found in 10 of 13 (77%) informative cases. AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH. These data indicate that nuclear beta-catenin expression is indicative for activated Wnt signalling and that neither AXIN1 gene mutations nor AXIN1 locus LOH are involved in Wnt pathway activation in GEJ adenocarcinomas.

Dataset Information

Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas.

Publications

Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas.

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