Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysplasia in Barrett's esophagus (BE) is a precursor to adenocarcinoma and most commonly occurs as a flat, grossly undetectable lesion. Rarely, dysplasia in BE may grow as a polypoid lesion. Most BE-associated polypoid dysplastic lesions have been referred to as "adenomas" because of their histological similarity to a colonic adenoma. BE-associated polypoid dysplastic lesions have been less well characterized than the flat type. Therefore, our aim was to characterize the clinicopathologic and molecular features of five cases of BE-associated polypoid dysplasia and to review the literature on this entity. The cases were evaluated clinically, histologically, immunostained for MIB-1 and p53, and genotyped for loss of heterozygosity (LOH) at the adenomatous polyposis coli (APC) locus. Mucosal biopsy specimens of five BE patients without dysplasia, and five BE cases with high-grade flat dysplasia, were used as controls. The study patients were all male (average age, 71 years) who presented with symptoms of gastroesophageal reflux disease. Endoscopically, all five cases had a well-defined sessile or pedunculated polypoid lesion ranging from 0.4 to 1.5 cm in size in the mid (n = 1) or distal (n = 4) esophagus and were associated with specialized-type BE (four long segment, one short segment). Histologically, the polyps consisted of intestinalized epithelium with low- and high-grade dysplasia. All five cases contained adenocarcinoma (four within the polyp, one in adjacent BE). All polyps showed increased cell proliferation in the form of surface MiB-1 staining and showed positive p53 staining. Three of three (100%) informative cases showed LOH at the APC locus in the dysplastic epithelium and in areas of adenocarcinoma. All five flat dysplasia controls also showed surface MIB-1 staining and p53 positivity, and three of three informative controls showed LOH for APC. None of the nondysplastic BE controls showed any of these findings. Three patients were treated with esophagectomy and two with polypectomy. All were alive, without metastasis, from 2 months to 6 years later. A literature review of esophageal "adenomas" uncovered 12 cases. Four of these had no clinical or pathological information, two were, in fact, gastric heterotopic lesions, one was composed entirely of intestinal-type epithelium, and five were polypoid dysplastic lesions similar to the cases described here (three male, two female; mean age, 59 years). Four of these five cases were associated with adenocarcinoma in the polyp (two intramucosal, two submucosal). In summary, BE-associated polypoid dysplasia share similar clinical, pathological, and molecular features as flat dysplasia and are often associated with adenocarcinoma. Thus, we agree with other authors who recommend that the term adenoma, which usually carries a benign connotation, be abandoned in favor of a descriptive diagnostic term, such as "BE-associated polypoid dysplasia." BE patients with this lesion should be considered strong candidates for esophageal resection similar to lesions of this kind that occur in inflammatory bowel disease.
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PMID:Polypoid dysplasia in Barrett's esophagus: a clinicopathologic, immunohistochemical, and molecular study of five cases. 1041 92

Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target beta-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low. The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation. A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett's esophagus, were included in this study. Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P<0.001). However, immunostaining failed to show aberrant nuclear localization of beta-catenin, a protein regulated by APC, in any of the polyps, irrespective of syndromic or sporadic types. Instead, positive membranous staining for beta-catenin was observed in all the cases. In addition, the expression characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been reported to be transcriptionally regulated by the APC/beta-catenin pathway, were similar in these two types of polyps. Furthermore, all cases, including those harboring dysplasia, showed negative nuclear staining for p53 and positive nuclear staining for retinoblastoma (RB). Taken together, these data show a lack of dysregulation in the APC/beta-catenin signaling pathway and in the expression of p53 and RB in fundic gland polyps despite a high frequency of somatic mutations of the APC and beta-catenin genes reported in these polyps. These findings may explain at least in part why fundic gland polyps show a negligible malignant potential even in the presence of dysplasia.
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PMID:Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps. 1501 89

Barrett's esophagus (BE) represents the most serious histological consequence of gastroesophageal reflux disease (GERD) that develops in 5-10% of patients with GERD. Given that BE is the only known precursor to esophageal adenocarcinoma (EA), a systematic endoscopic biopsy protocol can detect EAs at an early stage. However, endoscopic and histopathological evaluation of BE are not adequate for effective screening of high risk patients. Therefore, molecular abnormalities associated with BE have been considered as surrogate markers and their use as such is proposed. Flow cytometry is the most useful adjunct to histology, and ploidy status of BE is an independent risk factor. Cyclin D1 overexpression is inversely correlated with survival in EA. C-erbB2 (+) patients have poorer prognosis. High plasma adenomatous polyposis coli levels correlate with reduced patient survival. p53 expression allows patient risk for EA stratification. Nuclear factor-kappaB overexpression inversely correlates with good response to adjuvant chemotherapy and radiotherapy in EA. Patients with cyclooxygenase-2 overexpression have reduced survival rates. Increased E-cadherin staining is associated with shorter survival in EA patients who received chemoradiotherapy. Finally, existing data cannot rule out a correlation between EA and colorectal tumors. Seventeen BE molecular alterations yielded noteworthy clinical implications. Apart from endoscopy and histology, these data allow for better risk stratification for patients with BE and for more efficient and timely therapeutic approaches.
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PMID:New molecular concepts of Barrett's esophagus: clinical implications and biomarkers. 1585 73

Barrett's esophagus (BE) is an acquired condition in which the normal squamous epithelium in the distal esophagus is replaced by a metaplastic columnar epithelium, as a complication of chronic gastroesophageal reflux. The clinical significance of this disease is its associated predisposition to esophageal adenocarcinoma (EAC). Recently, and similarly to other human malignancies, the Wnt signaling pathway and its key component beta-catenin have been implicated in the carcinogenesis of BE. Although mutations in adenomatous polyposis coli (APC) or beta-catenin are rare in EAC, alterations of upstream components, such as overexpression of Wnt2 ligand or downregulation of Wnt antagonists may play dominant roles in the activation of the Wnt pathway. Increasing evidence suggests that inhibiting the Wnt pathway may be a new targeted therapy for the treatment of cancers and could, therefore, be promising for the cure of EAC, which remains a highly lethal disease.
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PMID:Targeting the Wnt signaling pathway to treat Barrett's esophagus. 1729 95

It is known that the predisposition to human disease is a mixture of inherited susceptibility and acquired exposure to environmental factors. Understanding gastrointestinal disease has indicated that germline adenomatous polyposis coli mutations predispose with a 99% certainty to colorectal cancer, whereas squamous esophageal cancer is caused by a combination of environmental exposures (including alcohol consumption, cigarette smoke, ingestion of contaminated preserved food) and/or infection (specifically with human papilloma virus), in most cases. Until now, despite the reasonably strong evidence for genetic risk from monozygotic twin studies for gastro-esophageal reflux disease (GERD), there have been no documented genetic targets in GERD. In this edition of the Journal, there is intriguing evidence that a common, single base-pair change in the secondary messenger gene GNbeta3 (i.e., a single-nucleotide polymorphism) may be important, perhaps through promoting abnormal perception of visceral pain in the esophagus. Other works link this genetic factor to functional dyspepsia, and these exciting preliminary lines of evidence are reviewed.
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PMID:Dissecting GI phenotype-genotype relationships in GERD and dyspepsia: an SNP here and an SNP there! 1917 93