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)

To clarify gene alterations in functional human adrenal tumors, we performed molecular analysis for p53 abnormalities in 23 cases with adrenal neoplasms. The immunohistochemical study with anti-p53 monoclonal antibody pAb1801 demonstrated that 10 of 23 (43.5%) cases overexpressed p53 protein in the tumor cells. Using a polymerase chain reaction-single strand conformation polymorphism study, 5 of 6 (83.3%) pheochromocytoma tissues (1 malignant and 5 benign) and 11 of 15 (73.3%) adrenocortical adenomas (2 with Cushing's syndrome and 13 with primary aldosteronism, all benign) showed an apparent electrophoretic mobility shift between the tumor and its paired adjacent normal adrenal tissue. Such differences were detected in exon 4 (12 cases), exon 5 (2 cases), and exon 7 (3 cases). The types of these mutations in exon 4 were a substitution from threonine (ACC) to isoleucine (ATC) at codon 102 in 5 cases, from glutamine (CAG) to histidine (CAC) at codon 104 in 1 case, from glycine (GGG) to alanine (CGG) at codon 117 in 1 case, from glutamate (GAG) to glutamine (CAG) at codon 68 in 1 case, and single base changes resulting in a premature stop codon at codon 100 in 2 cases. A 2-basepair deletion at codon 175 in exon 5 resulting in a frame shift was identified in 1 case. A single point mutation was identified, resulting in the substitution of glutamine (CAG) for arginine (CGG) at codon 248 of exon 7 in 1 case. A single basepair deletion at codon 249 resulted in a frame shift in 2 cases. There was 1 case with malignant pheochromocytoma that combined a single point mutation in exon 4 and a single base deletion in exon 7. Only 2 of 23 cases showed a loss of a normal allele encoding in the p53 gene. Northern blot analysis with 1.8-kilobase p53 cDNA revealed that p53 mRNA was overexpressed in 6 cases. Our results indicate that high frequencies of p53 gene mutation, especially in exon 4, exist in functional adrenal tumors. As p53 protein is a regulator of guanine nucleotide synthesis, the loss of normal inhibitory regulation by the p53 mutation would serve to increase the availability of GTP for the transduction of signals essential for increased cell growth and hormone expression in the adrenal tumors. These findings suggest that the p53 gene mutation may play a role in the tumorigenesis of benign and functional human adrenal tumors.
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PMID:Mutations of the p53 gene in human functional adrenal neoplasms. 810 38

The medical records and histologic documents of 14 patients treated at our institution for a thymic carcinoid tumor were reviewed. There were 3 women and 11 men with an age range from 35 to 71 years. One patient had a multiple endocrine neoplasia syndrome; another had a neurofibromatosis. Twelve tumors were revealed by local symptoms and two were asymptomatic. One patient had Cushing's syndrome that appeared secondarily and was related to metastases. Tumors ranged from 6 to 20 cm and had the characteristic histologic appearance of atypical carcinoid tumor. Immunohistochemical evaluations were done. Tumors were positive for cytokeratin (92%), neuroendocrine markers (100%), and p53 oncoprotein (29%). S-100 protein antibody revealed numerous sustentacular cells in one case. Overall survival was 46% and 31% at 3 and 5 years, respectively. However, all patients died of the disease within 109 months as a result of local progression (n = 5), local relapse (n = 3), distant metastases (n = 8), or a combination of these reasons. Median survival was 71, 30, and 5 months for patients who had total resection (n = 4), partial resection (n = 5), or simple biopsy (n = 4), respectively (p = 0.023). In conclusion, thymic carcinoid tumors can be considered thymic neuroendocrine carcinomas because of their malignant behavior and histologic appearance of atypical carcinoid tumors. Complete surgical resection offers the best hope for long-term survival.
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PMID:Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. 855 58

Recently, we have found a high frequency of p53 gene mutations in human functional adrenal tumours. As the tumorigenesis is a multigene defect, we believe that other oncogenes may also be involved in the initiation or progression of adrenal tumours. Using the single-strand conformational polymorphism (SSCP) method, we chose the ras oncogenes as the target in this screening procedure because their high mutation rates were detected in thyroid tumours. For the ras oncogenes analysed, exon 1 to exon 2 of H-ras and K-ras genes in the tumour tissues of 13 Conn's syndrome, two adrenal Cushing's syndrome, two non-functional adrenal tumours, one adrenocortical hyperplasia and eight phaeochromocytomas and its paired adjacent normal adrenal tissues were amplified and sequenced. No mutations were detected in the H-ras gene. But mutations of the K-ras gene were detected in 46% (6 of 13) of Conn's syndrome; the hot spots were located at codon 15, 16, 18 and 31, which were different from those previously found in other tumours (codon 12, 13 and 61). Northern blot analysis with 1.1 kb K-ras cDNA revealed that K-ras mRNA was more than tenfold over-expressed in four of Conn's syndrome, one case of Cushing's syndrome and one case of adrenocortical hyperplasia. The mutation sites and mutation type were not found in other tissues, which conferred that this was highly related to adrenocortical tumours. Yet, the correlation between K-ras oncogene and adrenocortical tumours needs to be clarified by further studies.
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PMID:Mutations of K-ras oncogene in human adrenal tumours in Taiwan. 956 40

The presence of p53 and tissue transglutaminase (tTG) gene expressions was investigated in human normal and pathologic adrenal tissues with two aims (1) to determine the tissue content of p53 protein, its messenger ribonucleic acid (mRNA) and, especially, tTG mRNA which has not been previously reported and (2) to study possible differences in the coexpression of p53 and tTG in various adrenal disorders. Using Northern blot analysis, p53 and tTG mRNAs were detected in each adrenal tissue examined including 5 normal human adrenals, 6 aldosterone-producing adenomas, 3 Cushing's adenomas, 1 primary nodular adrenocortical hyperplasia causing Cushing's syndrome in an infant, 12 non-hyperfunctioning adrenocortical adenomas, and 4 adrenocortical carcinomas. The results showed a significant positive correlation between these two mRNAs in all adrenal tissues except adrenocortical carcinomas. Compared to normal adrenals, high p53 mRNA levels were observed in aldosterone-producing and Cushing's adenomas and, most markedly, in a tissue from a primary nodular adrenocortical hyperplasia. Also, Cushing's adenomas had significantly higher tTG mRNA contents. Immunohistochemistry for wild-type and mutant p53 protein showed numerous p53 positive cells with a strong nuclear staining in a tissue from a primary nodular adrenocortical hyperplasia, whereas the p53 positive cells were absent, except those with a faint nuclear staining, in all other adrenal tissues. However, all adrenal tissues showed detectable p53 contents by the more sensitive method of luminometric immunoassay (LIA). Using this method, aldosterone-producing adenomas exhibited significantly higher p53 contents than normal adrenal tissues. These observations may support potentially important roles for p53 and tTG in adrenal pathophysiology, especially in mechanisms which influence the evolution and/or progression of aldosterone-producing and Cushing's adenomas and, most probably, hyperplasias.
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PMID:Coexpression of p53 and tissue transglutaminase genes in human normal and pathologic adrenal tissues. 971 8

To explore the clinical significance of p53 in the pathogenesis of adrenal neoplasms, we investigated the incidence of p53 gene mutations in functioning human adrenal tumours using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique to screen p53 exons 4 to 9. We examined 29 adrenocortical adenomas (primary aldosteronism, n=17; Cushing's syndrome, n=12, all benign), and 33 phaeochromocytomas (benign solitary, n=18; benign multiple, n=5; malignant, n=10) in Japanese and Chinese patients. PCR-SSCP did not show any abnormal band-shifts in any of the adrenocortical adenoma and benign solitary phaeochromocytoma tissues. In contrast, six phaeochromocytoma tissues (two cases benign multiple, four cases malignant) showed PCR-SSCP band-shifts. Subsequent DNA sequencing analysis of the shifted bands revealed six cases with nine mutations or intronic sequence alterations: three cases contained sequence alterations within intronic regions, three cases with silent mutation (sequence alteration in codon without amino acid alteration), and three cases contained missense mutations (one case each in exons 5, 6 and 9). Immunohistochemical staining demonstrated that two of three cases with missense mutations and one case with an intronic sequence alteration over-expressed p53 protein in tumour cell nuclei. We observed no association between p53 gene mutation and p21/WAF1/Cip-1 expression. The relatively high incidence of p53 gene mutations or intronic sequence alteration in multiple and malignant phaeochromocytomas, but not in benign solitary cases, suggests that p53 mutation could play some role in the pathogenesis of multiple and/or malignant phaeochromocytomas.
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PMID:The relatively high frequency of p53 gene mutations in multiple and malignant phaeochromocytomas. 979 65

The role of p53 tumor suppressor gene in the pathomechanism of adrenal tumors was investigated by measuring p53 protein and its messenger ribonucleic acid (mRNA) in 12 normal human adrenals as well as in 56 adrenal tumors (7 aldosterone-producing adenomas, 5 adrenocortical adenomas causing Cushing's syndrome, 19 non-hyperfunctioning adrenocortical adenomas, 5 adrenocortical carcinomas, 12 pheochromocytomas, 3 myelolipomas, 4 ganglioneuromas and 1 hemangioma). The p53 protein concentration was significantly increased in aldosterone-producing adenomas (394+/-36 pg/mg cytosolic protein, mean+/-SE, vs 266+/-18 in normal human adrenals), whereas the concentration of this protein in Cushing's adenomas, non-hyperfunctioning adrenocortical adenomas, pheochromocytomas, and in all but one adrenocortical carcinomas was similar to that measured in normal human adrenal tissues. One adrenocortical carcinoma tissue showed very high p53 protein content (3000 pg/mg cytosolic protein). By contrast, myelolipomas (23+/-20) ganglioneuromas (43+/-15) and a hemangioma (11 pg/mg cytosolic protein) had very low p53 protein content. Northern blot analysis revealed the presence of p53 mRNA in each adrenal tissue examined with highest levels in aldosterone-producing and Cushing's adenomas. It is possible that the differences in p53 protein and/or mRNA contents reflect corresponding differences in the pathogenetic importance of p53 alterations in these types of adrenal tumors.
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PMID:p53 protein and its messenger ribonucleic acid in human adrenal tumors. 997 75

Adrenocortical masses are among the most common tumors in humans. However, only a small proportion of these tumors cause endocrine diseases (such as primary hyperaldosteronism, hypercortisolism, hyperandrogenism, or hyperestrogenism), and less than 1% are malignant. In recent years, several of the molecular and cellular mechanisms involved in adrenal tumorigenesis have been unraveled. As a result, alterations in intercellular communication, local production of growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal tumor cells have been implicated in adrenal cell growth, hyperplasia, tumor formation, and autonomous hormone production. Genetic and chromosomal abnormalities, including several chromosomal loci and the genes coding for p53, p57, and insulin-like growth factor II, have been reported in adrenal tumors. In addition, chromosomal markers have been identified in several familial syndromes associated with adrenal tumors; these include menin, which is responsible for multiple endocrine neoplasia type I, and the hybrid gene that causes glucocorticoid-remediable hyperaldosteronism. Algorithms for endocrine testing and imaging procedures are now available to codify screening for, confirmation of, and differentiation of causes of primary hyperaldosteronism and the Cushing syndrome. Improved radiologic, computerized radiologic, and magnetic resonance imaging techniques, as well as selective catheterization studies, are useful in localizing adrenal tumors and in distinguishing between benign and malignant lesions and between functional and nonfunctional nodules. Finally, recent refinements in the field of minimally invasive general surgery have made laparoscopic adrenalectomy the method of choice for removing adrenal tumors; this type of surgery allows shorter hospital stays, lower morbidity rates, and faster recovery.
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PMID:Adrenocortical tumors: recent advances in basic concepts and clinical management. 1035 96

Adrenal cortical carcinoma (ACC) is a rare neoplasm that affects all age groups, with a bimodal peak of incidence, in young individuals in the first decade or two of life and in older subjects in the fifth to seventh decades. It may be clinically "functional" with Cushing's syndrome, virilization, or feminization, or it may be "nonfunctional." We report on the case of a 42-yr-old woman who complained of abdominal pain and a large adrenal tumor measuring 20 cm in size. No endocrine symptoms were observed. Laboratory tests showed increased levels of adrenocorticotropic hormone (ACTH), serum cortisol, and urinary free cortisol. Cytohistologic features were typical of ACC. A striking presence of hyaline cytoplasmatic globules was seen in cytologic smears and histologically, being immunoreactive for vimentin, consistent with an intracellular store of intermediate filaments. The tumor showed high proliferative activity (40%) with Ki-67 and negativity for p53, cerbB2, and bcl-2. Although hyaline globules are more frequent in pheochromocytomas and other neoplasms, they may also be present in ACC. These globules may be observed in cytologic smears. Also, the identification and immunohistochemical characterization of these hyaline globules in metastases may be useful in determining the origin of primary occult tumors. Diagn. Cytopathol. 1999;21:394-397.
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PMID:Giant adrenal cortical carcinoma, clinically "nonfunctional": report of a case containing cytoplasmic hyaline globules of vimentin. 1057 70

We reviewed 11 cases of primary thymic neuroendocrine carcinomas with combined features ranging from well-differentiated to poorly differentiated neuroendocrine carcinoma. For 3 asymptomatic patients, tumors were discovered during routine examination. Presentation in the other patients was as follows: Cushing syndrome, 2 patients; chest pain, 3 patients; superior vena cava syndrome, 1 patient; and hypercalcemia and hypophosphatemia, 1 patient. No clinical data were available for the 11th patient. All tumors were located in the anterior mediastinum and treated by surgical excision. The lesions were large and well-circumscribed with areas of hemorrhage and necrosis. They were characterized by areas showing a proliferation of monotonous, round tumor cells adopting a prominent organoid pattern admixed with areas showing sheets of atypical cells with hyperchromatic nuclei, frequent mitoses, and extensive areas of hemorrhage and necrosis. Immunohistochemical studies performed in 6 cases showed strong CAM 5.2 low-molecular-weight cytokeratin positivity in all cases, chromogranin and synaptophysin positivity in 4, Leu-7 in 3, and focal positivity for p53 in 2. Follow-up information for 9 cases showed that all patients died of their tumors between 1 and 4 years after diagnosis. The present cases highlight the heterogeneity of neuroendocrine neoplasms and reinforce the notion that these tumors form part of a continuous spectrum of differentiation.
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PMID:Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma. A clinicopathologic and immunohistochemical study of 11 cases. 1070 13

Twenty-two cases of oncocytic thymic neuroendocrine carcinomas (carcinoid tumors) are presented. The patients were 17 men and 5 women between the ages of 26 and 84 years (median, 55 years). Nine were asymptomatic, and the tumor was found on routine examination; four patients presented with chest pain, two with weight loss, two with multiple endocrine neoplasia I syndrome, and one with Cushing's syndrome. Surgical resection of the mediastinal tumor was performed in all cases. The lesions were described as soft, light tan to brown, measuring from 3 to 20 cm in greatest diameter. On cut section, the tumors showed a homogeneous surface, soft consistency, and focal areas of hemorrhage. Microscopically, the lesions were characterized by nests or trabeculae of tumor cells that contained abundant granular to densely eosinophilic cytoplasm, with round to oval nuclei and in some areas prominent nucleoli. Mitotic figures ranged from 2 to 10 per 10 high-power fields; foci of comedonecrosis were seen in all cases. Immunohistochemical studies including broad spectrum keratin, CAM 5.2, chromogranin, synaptophysin, Leu-7, and p53 were performed in 12 cases. All of the tumors were strongly positive for CAM 5.2 low-molecular-weight cytokeratin, 11 showed strong positive reaction for Leu-7, 10 for broad-spectrum keratin, 8 for chromogranin, 7 for synaptophysin, and only 1 case showed focal positive staining of the tumor cells for p53. Clinical follow-up of 14 patients showed that 10 were alive between 2 and 11 years, and 4 patients had died of tumor from 4 to 11 years after diagnosis. Patients with good clinical outcome were those whose tumors showed low mitotic activity and minimal nuclear pleomorphism, whereas those who had died of their tumors were those whose tumors were characterized by marked nuclear atypia and higher mitotic rates. Oncocytic thymic carcinoids should be added to the differential diagnosis of anterior mediastinal neoplasms characterized by a monotonous population of tumor cells with prominent oncocytic features.
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PMID:Primary neuroendocrine carcinoma (thymic carcinoid) of the thymus with prominent oncocytic features: a clinicopathologic study of 22 cases. 1082 19


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