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)

The p53 product is frequently mutated in human tumors. Both acquired and inherited mutations have been described. These mutations transform p53 from a growth suppressor gene to a transforming oncogene. We examined tissue from 6 patients with primary lung carcinoma and the corresponding brain metastases for the presence of p53 mutations by immunohistochemistry. We then confirmed and characterized the mutations by single strand conformation analysis and by direct sequence analysis. All 6 patients had primary and metastatic tumor expressing a mutant p53. The mutations were all G-T transversions and mapped to exons 5, 6, 7, and 8. The mutations in the primary tumors were precisely conserved in the brain metastases.
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PMID:p53 gene mutations in primary lung tumors are conserved in brain metastases. 133 52

Although it is widely accepted that tumor suppressor genes play an important role in the genesis and progression of human cancer, little is known about genetic events that accumulate during multistage lung carcinogenesis. Thus, to determine a subset of tumor suppressor genes that are involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), 22 brain metastases and 23 stage I primary lung tumors were examined for allelic losses at 40 loci on 10 chromosomes including the loci of 5 tumor suppressor genes, APC, WT1, RB, p53, and DCC. The incidence of allelic losses on chromosomes 3p, 13q, and 17p was high (> 60%) in both primary tumors and brain metastases. In brain metastases, a high incidence of allelic losses (> 60%) was also observed at loci on chromosomes 2q, 18q, and 22q, and the incidence of allelic losses on these chromosomes in brain metastases was significantly higher than that in primary tumors (P < 0.05). In two cases of brain metastases with corresponding primary lung tumors, sequential accumulation of allelic losses during progression of primary lung tumors was observed on several chromosomes including chromosomes 2q and 18q. These results indicate that, besides loss of heterozygosity for chromosomes 3p, 13q, and 17p, loss of heterozygosity for chromosomes 2q, 18q, and 22q also occurs frequently in advanced NSCLCS. Thus, it is possible that loss of heterozygosity on chromosomes 2q, 18q, and 22q occurs late in the progression of NSCLC and/or causes phenotypic alterations of NSCLC cells into more aggressive ones.
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PMID:Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma. 792 10

Ovarian cancer begins at a molecular level, however to date, our knowledge of genetic changes and mechanisms of ovarian tumorigenesis is limited. The natural history of ovarian cancer may depend on different anatomo-clinical and biological factors. In the life history of ovarian cancers the stage, histology, tumor grade, age of the patient and gene abnormalities, both oncogenes (c-myc, H-ra, new) and oncosuppressor genes (p53, in particular), DNA ploidy and steroid receptor status have important prognostic significance. Residual disease, when less than 1 cm, is another important prognostic factor, being significantly associated to the survival and, progression free, improvement in the survival. In the low stage ovarian cancer (Stage IA, IB, IAII,IBII,IC,IIA,IIB,IIC), adjuvant treatment seems not to influence Disease Free Survival (DFS) or Overall Survival (OS) The exception to this rule is when cisplatin regimen is assessed, as it can highly reduce the relapse rate while the survival is not significantly influenced. Ovarian cancers disseminate, primarily by continuity. Lymphatic dissemination to the pelvic and para-aortic lymph nodes (40% of patients at stage III-IV disease) as well as to the peritoneum is common. At the time of diagnosis, bone or brain metastases are rarely present and their presence is not related to the histology or grading of the tumor.
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PMID:Ovarian cancer: natural history and metastatic pattern. 915 59

The clinical and pathologic features of a rare case of follicular carcinoma with small foci of poorly differentiated and anaplastic carcinoma are presented. Eight years after the removal of the primary neoplasm, the patient developed pulmonary and brain metastases that were predominantly composed of the poorly differentiated and anaplastic components. A comparative immunohistochemical and molecular analysis of p53 status in the follicular, poorly differentiated and anaplastic components of the tumor was performed. p53 immunostaining was restricted to the poorly differentiated and anaplastic areas. Single strand conformation polymorphism analysis (SSCP-PCR) from DNA obtained by microdissection demonstrated the presence of a mutation (TAT-->TGT; Tyr-->Cys) in codon 220, exon six of the p53 gene in the anaplastic component, that was absent in the well-differentiated follicular areas. The results of that study in this rare tumor support that p53 has a tumor progression role in thyroid tumorigenesis.
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PMID:p53 in a thyroid follicular carcinoma with foci of poorly differentiated and anaplastic carcinoma. 918 95

The objectives of this study were to: (a) characterize the immunohistochemical expression of p53, bcl-2, E-cadherin (EC), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in brain metastases; (b) compare immunohistochemical (IHC) expression of brain metastases with their primary tumors; and (c) assess the prognostic value of expression of these markers. Tumors from 35 patients with brain metastasis were studied for IHC expression of p53, bcl-2, EC, MMP-9, and TIMP-1. In 17 cases, primary tumors were also available for study. In brain metastases, p53 was positive in 91% of cases and intermediate in 9%, MMP-9 was positive in all cases, TIMP-1 was intermediate in 6% and negative in 94% of cases, EC expression was positive in 86% of cases and intermediate in 14%, and bcl-2 was variable. All primary tumors were positive for p53 and MMP-9, 3% were intermediate for TIMP-1 and 97% were negative, 65% were positive for EC and 35% were intermediate, whereas bcl-2 expression was variable. Neither p53, bcl-2, TIMP-1, or EC staining correlated with overall survival or survival with brain metastases. No assessment of survival differences could be made for MMP-9 because of its overexpression in all tissues. This study found that MMP-9 and p53 were markedly overexpressed in primary tumors and matched brain metastasis, TIMP-1 expression was negative in the majority of specimens, whereas EC expression was maintained in both primary tumors and brain metastases and bcl-2 expression was variable. This study suggests that the functional balance of MMP-9 and TIMP-1 is shifted toward extracellular matrix degradation in brain metastases and that deregulation of cell cycle control by p53 also exists in brain metastases. The high expression of EC may indicate the importance of adherence at late stages of metastasis but requires further study.
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PMID:Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis. 1063 35

Symptomatic brain metastases of carcinomas in patients without a previously diagnosed malignancy are frequent in neurosurgical series. Such tumors often lack distinctive morphological characteristics so that the routine histological examination can be unsuccessful in identifying the site of origin. Objectives of the present study were to evaluate the frequency of brain metastases as the only manifestation of an unknown primary cancer by the retrospective analysis of a series of consecutively operated single cerebral metastases; to verify the efficacy of clinical investigations in detecting the site of origin; to investigate whether the primary site can be identified by the immunohistochemical study of the neurosurgical specimens. Antibodies to the following antigens were used: carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19.9, CA 125, BCA-225, cytokeratin 20, PSA, HMB-45. Out of 181 patients operated for single cerebral metastasis of carcinoma, 99 (54.7%) were in patients without any previously diagnosed systemic neoplasm. In 26.7% the primary remained undiagnosed after clinical investigations, in 9 cases even at autopsy. PSA and HMB45 antibodies specifically identified metastases from prostate carcinomas and skin melanomas, respectively. No other specific immunophenotype was identified; the immunoreactivity of the single cases was more or less suggestive for a primary site. Precocious metastases of lung carcinomas expressed CEA more frequently than late metastases. It has been hypothesized that CEA plays some role as a contact mediating device. CEA expression can have some link with the tendency to metastasize precociously to the brain. No major difference of p53 and k-ras expression has been found in precocious versus late brain metastases.
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PMID:Cerebral metastases as first symptom of cancer: a clinico-pathologic study. 1126 7

We report three patients with papillary thyroid carcinoma in whom fine-needle aspiration (FNA) showed neutrophils within tumor cells. All three patients presented with large neck masses; at excision, two proved to be tall cell variants of papillary cancer. Nodal metastasis, extrathyroidal extension, and vascular invasion were found in both cases. One patient has experienced recurrent disease; the other has an increasing thyroglobulin titer but no clinically appreciable recurrence. The third patient refused further therapy, but brain metastases were noted clinically; this patient died of disease. In each case, FNA showed tumor clusters with characteristic nuclear features, papillary groups, and psammoma bodies. Neutrophils were present in the cytoplasm of tumor cells in the absence of necrosis. Immunostaining for proliferating cell nuclear antigen (PCNA), MIB-1 (Ki-67), and p53 tumor suppressor gene product was markedly positive. lntraepithelial neutrophils have not been previously reported in differentiated thyroid tumors. We postulate that these neoplasms produce specific leukocyte-attracting cytokines analogous to those produced by anaplastic and poorly differentiated thyroid carcinomas. We believe the finding of intraepithelial leukocytes in the absence of necrosis in thyroid FNA specimens represents a characteristic of clinically aggressive differentiated papillary neoplasms; in our small series, each represented a tall cell variant of papillary carcinoma.
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PMID:Intraepithelial Neutrophils in Thyroid Fine-Needle Aspiration: A Portent of Aggressive Thyroid Cancer? 1211 79

The aberrant methylation of the CpG island promoter regions acquired by tumor cells is one mechanism for loss of gene function. The high methylation rate for RB1 and death-associated protein-kinase gene (DAP-kinase) (60 and 90%, respectively) previously found in brain metastases suggests this mechanism could be non-randomly associated to tumor progression and metastasis. Thus, in addition to these two genes, we determined the methylation status of the genes p16INK4a, glutathione S-transferase P1 (GSTP1), O6-methylguanine DNA methyltransferase (MGMT), thrombospondin-1 (THBS1), p14ARF, TP53, p73, and tissue inhibitor of metalloproteinase 3 (TIMP-3), in 18 brain metastases of solid tumors, with methylation specific PCR. The metastases were derived from malignant melanoma (three cases), lung carcinoma (six cases), breast carcinoma (three cases), ovarian carcinoma (two cases) and one each from colon, kidney, bladder and undifferentiated carcinoma. We detected methylation levels in the tumor samples of 83% in p16INK4a, 72% in DAP-kinase, 56% in THBS1, 50% in RB1, 39% in MGMT, 33% in GSTP1 and p14ARF each, 22% in p73 and TIMP-3 each, and 11% in TP53. The methylation index (number of genes methylated/number of genes tested) varied between 0.1 and 0.6, with an average of 0.42, indicating that a high grade of gene methylation accumulates parallel to the tumor metastasis process. Our data suggest an important role for gene methylation in the development of brain metastases, primarily involving epigenetic silencing of DAP-kinase, THBS1 and the cell-cycle regulators RB1/p16INK4a.
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PMID:Promoter methylation status of multiple genes in brain metastases of solid tumors. 1465 77

O6-methylguanine-DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. By removing alkyl groups from the O6-position in guanine, MGMT can prevent G:C to A:T transition mutations, a type of variation frequently involving TP53 mutations in brain tumors. Promoter hypermethylation of CpG islands in tumor-related genes can lead to their transcriptional inactivation, and this epigenetic mechanism has been shown to participate in MGMT silencing in some cancers, including those affecting the nervous system. Accordingly, a link between both genetic and epigenetic anomalies may exist in these neoplasms. To determine the relevance of defective MGMT function due to aberrant methylation in relation to the presence of TP53 mutations, we studied 469 nervous system tumors (including all major histological subtypes) for MGMT promoter methylation and TP53 mutations at exons 5-8. Overall, aberrant methylation occurred in 38% of the samples (180/469), with values higher than 50% in the more malignant forms such as glioblastomas and anaplastic gliomas including those with astrocytic, oligodendroglial and ependymal differentiation. In contrast, the non-glial tumors displayed an overall aberrant MGMT promoter methylation of 26%, even though this group includes highly malignant tumors such as neuroblastomas, medulloblastomas and brain metastases. Overall, TP53 mutations were found in 25% of the methylated MGMT tumors (45/180), whereas only 10% of the unmethylated MGMT tumors (30/289) showed TP53 changes (P < 0.001). G:C to A:T changes occurred at CpG sites in 9% of methylated tumors, and in 0.7% of the unmethylated samples. This type of transition at non-CpG dinucleotides was also more frequent in the tumors with aberrant MGMT methylation (5%) than the unmethylated tumors (0.7%). These data suggest that MGMT silencing as a result of promoter hypermethylation may lead to G:C to A:T transition mutations in the TP53 gene of some histological nervous system tumor subtypes.
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PMID:Hypermethylation of the DNA repair gene MGMT: association with TP53 G:C to A:T transitions in a series of 469 nervous system tumors. 1545 Apr 1

This study, using tissue microarrays, aimed at the immunomorphologic profiling of nonsmall cell lung cancer (NSCLC) cases to reveal clinically relevant disease groups and biomarkers associated with patients' survival and tumor progression including brain metastatic potential. Donor tissue blocks were form 59 patients, including 33 primary tumors without distant metastasis and 26 brain metastatic primary tumors as well as the brain metastases. Sections were immunostained for 29 markers targeting molecules of cell adhesion, cell growth, cell cycle, and apoptosis regulation. beta-Catenin expression was the only independent prognostic marker associated with better outcome. Elevated expression of collagen XVII, CD44v6, and caspase-9, and the reduced production of beta-catenin and cellular apoptosis susceptibility protein were significantly associated with the metastatic potential of primary NSCLC. Expression of positive cell cycle regulators cyclin D1 and cyclin D3 was also increased in metastatic primary tumors. Metastatic tumor progression into the brain was accompanied by prominent p16, syndecan-1, p53 (DO7), and caspase-3 protein levels. Hierarchical clustering of complex immunoprofiles based on the differentially expressed markers grouped NSCLCs of the poorest outcome with high correlation including 2/3 of brain metastases of mixed histology. The brain metastatic potential of NSCLCs may be linked to the elevated levels of cyclinD1, cyclinD3, p16, p53, caspase-3, caspase-9, CD44v6, and collagen XVII and the down-regulation of beta-catenin and cellular apoptosis susceptibility protein. Unsupervised immunoprofiles based on differentially expressed biomarkers may help selecting lung cancers with aggressive behavior.
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PMID:Immunophenotypic profiling of nonsmall cell lung cancer progression using the tissue microarray approach. 1753 3


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