Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus.

To determine the relevance of MGMT in Barrett's carcinogenesis, we analyzed promotor hypermethylation and expression of MGMT in Barrett's adenocarcinomas and its paired precursor lesions from 133 patients using a methylation-specific PCR, real-time RT-PCR and immunohistochemistry. Hypermethylation was detected in 78.9% of esophageal adenocarcinomas, in 100% of Barrett's intraepithelial neoplasia, in 88.

Cofactor of BRCA1: a novel transcription factor regulator in upper gastrointestinal adenocarcinomas.

Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs.

Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis.

Chronic gastroesophageal reflux disease is a known risk factor for Barrett's esophagus (BE), which induces oxidative mucosal damage. Glutathione peroxidase-3 (GPx3) is a secretory protein with potent extracellular antioxidant activity. In this study, we have investigated the mRNA and protein expression of GPx3, and explored promoter hypermethylation as an epigenetic mechanism for GPx3 gene inactivation during Barrett's carcinogenesis.

Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas.

We show the molecular mechanisms involved in Darpp-32 overexpression and its biological role in upper gastrointestinal adenocarcinomas (UGC). A tumor tissue array of 377 samples was developed and used to detect DARPP-32 DNA amplification and protein overexpression, which occurred in 32% and 60% of UGCs, respectively. Concomitant overexpression of mRNA for Darpp-32 and its truncated isoform t-Darpp was observed in 68% of tumors (P < 0.

Expression of tight-junction protein claudin-7 is an early event in gastric tumorigenesis.

Trefoil factor-1 (Tff1) expression is remarkably down-regulated in nearly all human gastric cancers. Therefore, we used the Tff1 knockout mouse model to detect molecular changes in preneoplastic gastric dysplasia. Oligonucleotide microarray gene expression analysis of gastric dysplasia of Tff1-/- mice was compared to that of normal gastric mucosa of wild-type mice.

Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.

Gene expression profiling of anatomically diverse carcinomas and their corresponding normal tissues was used to identify genes with cancer-associated expression. We show here that the ubiquitin conjugase, UbcH10, is significantly overexpressed in many different types of cancers and is associated with the degree of tumor differentiation in carcinomas of the breast, lung, ovary and bladder, as well as in glioblastomas. We also show that UbcH10 overexpression in gastro-esophageal, and probably other carcinomas may be a direct consequence of chromosomal amplification at the UbcH10 locus, 20q13.

CpG island methylation in Schistosoma- and non-Schistosoma-associated bladder cancer.

Urothelial carcinomas (TCC) constitute the vast majority of bladder cancers in most of the world. On the other hand, squamous cell bladder carcinoma, a rare subtype in the Western world, is a common subtype in areas with endemic Schistosoma infection. Although schistosomal infection has been reported to influence DNA methylation, the pattern and extent of CpG island hypermethylation in squamous cell carcinomas remain unknown.

Clustering of molecular alterations in gastroesophageal carcinomas.

Gene expression levels are regulated at many levels. Integration of genome-wide analyses for the study of DNA and RNA provides a unique tool to detect genetic alterations in the cancer genome. In this study, we generated and integrated DNA amplification data from comparative genomic hybridization (CGH) and serial analyses of gene expression (SAGE) in order to obtain a molecular profile of gastroesophageal junction (GEJ) carcinomas.

Coamplified and overexpressed genes at ERBB2 locus in gastric cancer.

DNA copy number amplification at the chromosomal region of 17q is frequent in gastric cancer. Recently 17q21 was identified as the critical region for the amplicon formation because this region harbors the ERBB2 oncogene and several other targets, such as TOP2A and DARPP32. In our study, we characterized the amplification (52 cases) and expression (29 cases) levels of ERBB2, TOP2A and DARPP32 in gastric cancer samples.

Decreased abundance of trefoil factor 1 transcript in the majority of gastric carcinomas.

Background: Gastric carcinoma is one of the leading causes of cancer-related death worldwide, but the mechanisms underlying its development and progression still remain largely uncharacterized. As loss of trefoil factor 1 (TFF1) expression leads to neoplastic growth in the antropyloric mucosa of mice, the authors sought to comprehensively study the human TFF1 gene in primary gastric carcinomas.

Methods: The authors studied the human TFF1 gene in primary gastric carcinomas and normal gastric mucosa at the DNA, RNA, and protein levels through DNA sequencing, quantitative real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry.

Overexpression of the 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein in common adenocarcinomas.

Background: The 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein (DARPP-32) is the only known protein that can act as a protein phosphatase-1 inhibitor or a protein kinase inhibitor. It is known as a neurogenic protein that plays a major role in dopamine regulation in the central nervous system. Recently, DARPP-32 and a truncated isoform, t-DARPP, have been cloned in gastric carcinoma.

Magnetic resonance imaging of gastric cancer in Tff1 knock-out mice.

In this work, the use of MRI to stage gastric neoplasia in a mouse model of spontaneous gastric cancer is demonstrated. The methodology involves 1) the use of deuterated water ((2)H(2)O) to distend the stomach, and to provide negative contrast between the stomach and the lumen without inducing susceptibility-based field shifts; 2) GlucaGen to minimize motion artifacts that arise from peristalsis; and 3) Gd-DTPA to enhance contrast between the dysplasia/tumor and the normal wall. Initial images are presented from a Tff1 -/- homozygous knock-out model of gastric cancer and a heterozygous C57BL6/J control mouse.

Hypermethylation of metallothionein-3 CpG island in gastric carcinoma.

The expression of metallothionein (MT)-3 is often markedly reduced in gastric carcinoma (GC). The molecular mechanism of this MT-3 downregulation is unknown. Transcriptional silencing of MT-3 by methylation of CpG island was investigated by nucleotide sequencing and denaturing high performance liquid chromatography (DHPLC) analyses.

Gastric cancers overexpress S100A calcium-binding proteins.

Serial analysis of gene expression provides quantitative and comprehensive expression profiling in a given cell population. In our efforts to define the genes overexpressed in carcinoma of the stomach, we performed serial analysis of gene expression analyses on dissected neoplastic and normal gastric epithelia. We identified 91,334 expressed tags, including 26,633 that were unique.

Molecular and biologic basis of upper gastrointestinal malignancy. Gastric carcinoma.

Gastric cancer is one of the world's most common cancers and is a leading cause of cancer death worldwide. Neoplasia of the stomach is mainly composed of adenocarcinomas, which for more than 95% of cases. Although mesenchymal tumors (i.

Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP.

Gastric carcinoma is the second most common cause of cancer-related death worldwide. Recently, we have demonstrated that expressed sequence tag AA552509 was frequently amplified and the most consistently overexpressed target at 17q in gastric cancers. Herein, we report that DARPP-32 (dopamine and cAMP-regulated phosphoprotein of M(r) 32,000) is the target gene for overexpression of expressed sequence tag AA552509.

Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review.

This paper reviews data on the prognosis of gastrointestinal stromal tumors (GISTs). These tumors are specific KIT-expressing and KIT-signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. GISTs occur in the entire gastrointestinal (GI) tract and may also arise from the omentum, mesenteries, and retroperitoneum.

Clinical management of gastrointestinal stromal tumors: before and after STI-571.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Until recently, surgery has been the only effective therapy for GIST. However, even after complete resection of tumor, many patients still eventually die of disease recurrence.

Targets of gene amplification and overexpression at 17q in gastric cancer.

DNA copy number gains and amplifications at 17q are frequent in gastriccancer, yet systematic analyses of the 17q amplicon have not been performed. In this study, we carried out a comprehensive analysis of copy number and expression levels of 636 chromosome 17-specific genes in gastric cancer by using a custom-made chromosome 17-specific cDNA microarray. Analysis of DNA copy number changes by comparative genomic hybridization on cDNA microarray revealed increased copy numbers of 11 known genes (ERBB2, TOP2A, GRB7, ACLY, PIP5K2B, MPRL45, MKP-L, LHX1, MLN51, MLN64, and RPL27) and seven expressed sequence tags (ESTs) that mapped to 17q12-q21 region.

Molecular biology of gastric cancer.

Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumors, whereas gastrointestinal stromal tumors (GISTs) are the most common neoplasms of the rare gastric mesenchymal tumors. Although the incidence of mid-distal gastric adenocarcinomas is decreasing, the incidence of gastroesophageal junctional tumors and Barrett's adenocarcinomas is increasing for unknown reasons.

Accurate, noninvasive detection of Helicobacter pylori DNA from stool samples: potential usefulness for monitoring treatment.

A novel DNA assay demonstrating sensitive and accurate detection of Helicobacter pylori from stool samples is reported. Moreover, in three individuals tested for therapeutic response, the assay showed the disappearance of H. pylori DNA during treatment.