Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Esophageal cancer is an important problem in the United States. It results in more deaths (over 10,000 annually) than rectal cancer. Furthermore, the incidence of esophageal adenocarcinoma is increasing at a rate faster than that of nearly any other cancer and the reasons for the increase are not well understood. A variety of tumor-suppressor genes (including p53, APC, DCC and Rb) and proto-oncogenes (including prad1, EGFR, c-erb-2 and TGF alpha) may be involved in the development and progression of esophageal cancer. Clinical prognostic factors include stage, Karnofsky performance status, sex, age, anatomic location of the tumor, and degree of weight loss. A new staging system based on depth of wall penetration and lymph node involvement correlates well with prognosis for patients undergoing esophagectomy. Newer staging procedures including endoscopic ultrasound as well as the use of minimally invasive surgery, such as thoracoscopy and laparoscopy, may allow accurate staging without esophagectomy. Surgical resection provides excellent palliation; however, the chance for cure with esophagectomy alone is only 10% to 20%. Adjuvant treatment with pre- or postesophagectomy radiation may improve local-regional control but does not improve survival. Nor has preoperative chemotherapy been shown to improve survival; however, it remains an active area of investigation. Multimodality therapy, namely, chemotherapy and radiation (chemoradiation), given concurrently prior to surgical resection shows promise, with one study indicating a 5-year survival of 34%. A complete pathologic response to chemoradiation correlates with improved survival. Chemoradiation has been shown to be superior to radiation as primary management of esophageal cancer. There has been no successfully completed randomized trial of surgery versus definitive radiation or chemoradiation. However, chemoradiation represents a reasonable alternative to esophagectomy in the primary management of squamous cell carcinoma of the esophagus and chemoradiation also appears to be effective in the treatment of patients with adenocarcinoma of the esophagus, offering significant palliation and a chance for long-term survival as well. Randomized studies of preoperative chemoradiation versus surgery or versus chemoradiation alone are needed. The treatment of advanced esophageal cancer must be directed toward palliation of symptoms. Newer endoscopic techniques, including the use of expansile metal stents, laser ablation, intraluminal high-dose rate brachytherapy, BICAP tumor probe, or photodynamic therapy, offer selected patients short-term palliation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Esophageal cancer. 753 69

Esophageal adenocarcinoma is a virulent malignancy that is rapidly increasing in incidence. Overexpression of p53, a tumor-suppressor gene with prognostic significance in many malignancies, has not been adequately evaluated in this disease. The purpose of this study was to evaluate the pattern and importance of p53 protein accumulation in patients with esophageal adenocarcinoma. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue from 24 patients, all of whom had early stage disease. Nineteen of 24 patients underwent surgery, and 16 had complete tumor resection. p53 oncoprotein immunoreactivity was demonstrated in 50% (12/24) of patients overall and 50% (8/16) of patients undergoing esophagectomy. p53 overexpression was more common in patients with well-differentiated tumors (P = 0.07). The tissue surrounding tumor stained positive for p53 in six patients, four of whom had no evidence of Barrett's epithelium. Among the 16 patients who underwent esophagectomy, those whose tumors demonstrated p53 overexpression had a longer overall (28 vs. 13.5 months) and disease-free (24.3 vs. 13 months) median survival. The difference in disease-free survival was significant (P = 0.05). Our findings suggest that p53 overexpression may serve as a marker of improved survival in patients with esophageal adenocarcinoma.
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PMID:p53 correlates with improved survival in patients with esophageal adenocarcinoma. 772 72

The WAF1 (CIP1/SDI1) gene encodes a cyclin-dependent kinase inhibitor which is induced by wild-type, but not mutated, p53 gene product. WAF1 immunohistochemistry has been suggested to clarify the phenotype of overexpressed p53 gene product. We evaluated both p53 and WAF1 gene products by immunohistochemistry in 98 esophagectomy specimens with Barrett esophagus and/or adenocarcinoma of the esophagus and esophagogastric junction. Diffuse positive p53 staining was found in 40 of 88 adenocarcinomas (45%) and in dysplastic Barrett epithelium in 20 of 65 cases (31%), but not in Barrett mucosa without dysplasia (n = 36, P = .0004). Eighty-eight percent of cancers exhibited WAF1 expression, but there was no association with p53 and WAF1 staining. WAF1 protein was also identified in Barrett epithelium and in esophageal squamous and gastric epithelium. In contrast to carcinomas, a unique pattern of mutually exclusive p53 and WAF1 expression was found in five cases of dysplastic Barrett epithelium; a missense mutation at codon 175 of p53 was identified in one. p53 staining of adenocarcinoma was associated with shorter patient survival but was not independent of stage; WAF1 status added no prognostic information. Our findings show that WAF1 immunohistochemistry complements p53 immunohistochemistry in some cases of Barrett dysplasia but not in adenocarcinomas. Positive p53 immunostaining can serve to confirm a neoplastic process in Barrett mucosa. Positive staining of adenocarcinomas may be an indication of advanced stage.
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PMID:p53 and p21(WAF1/CIP1/SDI1) gene products in Barrett esophagus and adenocarcinoma of the esophagus and esophagogastric junction. 891 33

Barrett's esophagus, or specialized intestinal metaplasia, is a common condition associated with gastroesophageal reflux and an increased risk for adenocarcinoma of the esophagus and gastric cardia. Currently, clinical surveillance for early detection of adenocarcinoma relies on the histopathological assessment of dysplasia. In this review we present data from the published literature, and combine this with results from our own research, to address what is currently known about the environmental factors and the molecular changes thought to be important in the pathogenesis of Barrett's esophagus. The most important and well-characterized molecular changes, preceding the development of dysplasia, are alterations in the p53 and erbB-2 genes and aneuploidy. These molecular changes, as well as environmental influences, such as the quality and quantity of gastroduodenal refluxate, may result in abnormal cell proliferation which in turn promotes further genetic abnormalities and deregulation of cell growth. The identification of molecular changes, in the context of predisposing environmental factors, will enhance our understanding of the malignant progression of Barrett's esophagus leading to more effective surveillance and treatment.
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PMID:Recent developments in the molecular characterization of Barrett's esophagus. 957 72

Esophageal adenocarcinoma (SKGT-2, SKGT-4, and SKGT-5) and epidermoid carcinoma (HCE-4) cells containing variable retinoblastoma (Rb), cyclin D1, p16, and p53 expression patterns were exposed to the synthetic flavone, flavopiridol. The IC50 was approximately 100-150 nM for each of these cell lines. Exposure of esophageal carcinoma cells to 300 nM flavopiridol induced cell cycle arrest and apoptosis, resulting in a 90% inhibition of proliferation relative to that of nontreated cells after a 5-day exposure to the drug. Western blot analysis revealed diminution of cyclin D1, Rb, and p107 protein levels after flavopiridol exposure. Whereas cell cycle arrest and overall growth inhibition did not correlate in any obvious manner with the genotype of these cell lines, apoptosis seemed to be more pronounced in SKGT-2 and SKGT-4 cells that lack Rb expression. Pretreatment of esophageal cancer cells with 9-cis-retinoic acid did not substantially potentiate flavopiridol activity in these cell lines. Although the precise mechanism of flavopiridol-mediated cytotoxicity has not been fully defined, this drug is an attractive agent for molecular intervention in esophageal cancers and their precursor lesions; further evaluation of flavopiridol in this clinical context is warranted.
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PMID:Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. 982 56

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion, Barrett's metaplasia. Despite advances in multimodality therapy, the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis, therapy, and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis, allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes, may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future.
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PMID:Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. 1023 32

Barrett's esophagus is a precancerous condition in which the squamous esophageal epithelium is replaced by a columnar epithelium. Although different types of columnar epithelium have been described, the most frequently encountered is specialized columnar epithelium or intestinal metaplasia. Most investigators believe that increased cancer risk is only associated with this type. Esophageal adenocarcinoma is increasing in frequency in the United States and in Western Europe. Recent studies highlight the importance of gastroesophageal reflux disease in esophageal adenocarcinoma. Bile-acid reflux may also play a role. Increasing interest has been expressed in short-segment (2-3 cm) Barrett's esophagus. The contribution of short-segment Barrett's esophagus to cancer at the gastroesophageal junction is currently being studied. Although regular surveillance is often recommended, the commonness of Barrett's esophagus makes such a practice impractical for every patient. Biomarker development is needed to identify patients at greatest risk, with p53 a promising candidate based on recent studies. Initial data suggest that redox mechanisms may be involved in Barrett's esophagus. Several methods have recently been described for reversing Barrett's esophagus to squamous epithelium, but the significance of this practice in terms of reducing cancer risk remains to be demonstrated.
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PMID:Recent developments in Barrett's esophagus. 1112 53

Gastroesophageal reflux disease (GERD) and columnar-lined esophagus with intestinal metaplasia (Barrett's esophagus) are the major recognized risk factors for adenocarcinoma of the esophagus. The American College of Gastroenterology recommends that patients with long-standing GERD symptoms (particularly those 50 years of age or older) undergo endoscopic screening to identify Barrett's esophagus and that those patients who have Barrett's esophagus undergo regular endoscopic surveillance. These recommendations are made with the expectation that screening and surveillance will decrease mortality from esophageal cancer, although this association is unclear. Nonetheless, retrospective studies have shown that endoscopic surveillance can detect some early, curable neoplasms in patients with Barrett's esophagus. Dysplasia in Barrett's esophagus is widely regarded as the precursor of invasive malignancy. Although grading dysplastic changes is largely subjective, dysplasia remains the most appropriate biomarker for clinical evaluation of Barrett's esophagus. Flow-cytometric and p53 abnormalities may be earlier and more specific markers for cancer development, but application of these abnormalities is not yet recommended for clinical practice. Endoscopic surveillance also is adversely affected by biopsy sampling error. Techniques that may minimize biopsy sampling error include chromoendoscopy, endosonography, optical coherence tomography, and fluorescence detection techniques. Further studies are needed to clearly define the role of these techniques in surveillance, and none is practical for routine clinical use at this time. Although not specifically recommended, experimental ablative therapies, such as photodynamic therapy, can be considered by physicians for their patients with high-grade dysplasia in Barrett's esophagus, if they are provided as part of an established, approved research protocol.
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PMID:Screening and surveillance for complications related to gastroesophageal reflux disease. 1174 38

We investigated TP53 mutation patterns in cancers of the esophagus and cardia of patients coming from Lower Normandy, a region situated in the highest incidence area in Europe. To screen tumor samples, we first used denaturing gradient gel electrophoresis (DGGE), a well-characterized technique which constituted our reference method. Then the results were compared with those obtained by denaturing high performance liquid chromatography (DHPLC), a recent and automatic screening technology. Analysis of the TP53 mutations profile showed that the detected alterations were mainly point mutations. Ninety-seven percent (33/34) of esophageal squamous cell carcinoma samples presented at least one mutation or polymorphism. The proportion of somatic, non-silent and sequence-confirmed mutations was 76% (26/34). The most common substitutions were G-->A transitions, which could be related to nitrosamines, acetaldehyde or factors prone to producing mucosal irritation, like hot beverages. G-->T transversions, which were also frequently detected, could originate from benzo[a]pyrene in tobacco smoke. A-->T transversions were not revealed in our series, which constitutes a discordance with mutational spectra already performed in north-western France. Concerning adenocarcinoma of the esophagus and cardia, the alteration frequency was 69% (11/16), with a majority of G-->A transitions at CpG dinucleotides. They are probably related to endogenous process mediated by inflammatory diseases like gastro-esophageal reflux and Barrett's esophagus. The main advantage provided by DHPLC was its ease of application. However, the optimization steps turned out to be quite critical, especially for sequences with high melting temperatures embedded in lower melting temperature fragments. Considering only the common sequences analyzed by the two techniques, four of the 46 positive samples detected by DGGE were not revealed by DHPLC. This result stresses the limited sensitivity of DHPLC compared with DGGE under the conditions described in this study.
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PMID:Simultaneous use of DGGE and DHPLC to screen TP53 mutations in cancers of the esophagus and cardia from a European high incidence area (Lower Normandy, France). 1271 98

Barrett's esophagus is a recognized risk factor for adenocarcinoma of the esophagus. Dysplasia in Barrett's epithelium is considered a precursor to malignancy. Several tumor suppressor genes, including p53, have recently been implicated in the pathogenesis of esophageal adenocarcinoma. However, the interval between the development of Barrett's esophagus, dysplasia, and frank malignancy is usually very long. A case of adenocarcinoma of the esophagus arising from Barrett's esophagus in a 25-year-old man is discussed. Point mutation in exon 8 of p53 was discovered in this patient's tumor and surrounding dysplastic Barrett's mucosa. To our knowledge, this is the youngest reported case of Barrett's-associated esophageal adenocarcinoma in the medical literature. It suggests that acquired somatic mutations in tumor suppressor genes may occur early in life and that these mutations may contribute to the development of dysplasia and cancer in Barrett's esophagus.
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PMID:Barretts carcinoma in a 25-year-old man with point mutation of the p53 tumor suppressor gene. 2158 41


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