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)

Granular cell astrocytomas (GCA) are an uncommon morphologic variant of infiltrative glioma that contains a prominent population of atypical granular cells. As a rule, they are biologically aggressive compared to similar tumors without granular features. We sought to determine whether GCAs possess distinct genotypic alterations that might reflect their unique morphology or clinical behavior. Eleven GCAs occurring in 7 men and 4 women ranging in age from 46 to 75 years were investigated for genetic alterations of known significance in glial tumorigenesis, including LOH at 1p, 9p, 10q, 17p, and 19q, point mutations of TP53, deletions of p16(CDKN2A) and p14ARF, as well as EGFR amplifications. Tumors included had an infiltrative growth pattern and consisted of large, round cells packed with eosinophilic, PAS-positive granules that varied in quantity, ranging from 30 to 100% of tumor cells. Three tumors were of WHO grade II, one was grade III, and 7 were grade IV lesions. Overall, the tumors showed higher frequencies of LOH at 1p, 9p, 10q, 17p, and 19q than typical infiltrating astrocytomas of similar grades. Losses on 9p and 10q occurred in nearly all cases, including low grade lesions. TP53 mutations were identified in 2 grade IV GCAs, while combined p14ARF and p16(CDKN2A) homozygous deletions were noted in only one grade IV lesion. None showed EGFR amplification. We found no genetic alterations specific for GCA. Instead, it appears that granular cell change occurs across genetic subsets. The high frequency of allelic loss, especially on 9p and 10q, may confer aggressive growth potential and be related to their rapid clinical progression.
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PMID:Granular cell astrocytomas show a high frequency of allelic loss but are not a genetically defined subset. 1274 72

Genome-wide copy number profiles were characterized in 41 primary bladder tumors using array-based comparative genomic hybridization (array CGH). In addition to previously identified alterations in large chromosomal regions, alterations were identified in many small genomic regions, some with high-level amplifications or homozygous deletions. High-level amplifications were detected for 192 genomic clones, most frequently at 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2), and 19q13.1 (CCNE). Homozygous deletions were detected in 51 genomic clones, with four showing deletions in more than one case: two clones mapping to 9p21.3 (CDKN2A/p16, in nine cases), one at 8p23.1 (three cases), and one at 11p13 (two cases). Significant correlations were observed between copy number gain of clones containing CCNE1 and gain of ERBB2, and between gain of CCND1 and deletion of TP53. In addition, there was a significant complementary association between gain of CCND1 and gain of E2F3. Although there was no significant relationship between copy number changes and tumor stage or grade, the linked behavior among genomic loci suggests that array CGH will be increasingly important in understanding pathways critical to bladder tumor biology.
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PMID:Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. 1278 93

The RB1 pathway and the p53 pathway represent important, interconnected biochemical units frequently perturbed in human cancer. Essential tumor protective mechanisms, such as cellular growth control and apoptosis, are regulated through these systems. Comprehensive studies of these pathways, including most known pathway components, have not been performed in NHL. We therefore analyzed the involvement of aberrations of these pathways in NHLs from the population-based West-Danish NHL registry, LYFO registry, as well as in a series of neurofibromatosis 1-related tumors. The aim of the studies was to obtain information about extent and interrelation of alterations of pathway components, as well as clinical information such alterations might provide. We found that alteration of components of one or both of these pathways are very common, occurring in the vast majority of DLCLs. Our data suggest that the pathways are not entirely linear in lymphomagenesis. The p53 pathway components MDM2 and p53 were frequently altered in the same lymphoma indicating that the role of MDM2 in lymphomagenesis is not entirely dependent on the downstream target, p53. The linearity of the RB1 pathway was clearer as only 1 of 34 DLCLs showed aberration of more than one of the components cyclin D3, p16INK4A, and pRB. An intriguing novel observation was that p16INK4A inactivation was associated with increased expression of cdk4, a kinase target of p16INK4A inhibitory function. This could indicate the existence of a regulatory feedback loop between p16INK4A and cdk4. Cyclin D3 has yet to be established as an oncoprotein. Our finding of cyclin D3 overexpression in a significant number of DLCLs (including all thyroid lymphomas analyzed), as well as the intimate inverse relation to other RB1 pathway alterations suggest, that cyclin D3 is important in lymphomagenesis. However, further studies are needed to implicate cyclin D3 definitively as an oncoprotein. Our data contain several lines of evidence supporting roles of CDKN2A and MDM2 in progression of neoplastic disease. We found that loss of p16INK4A coincided with transformation of neurofibromas to malignant peripheral nerve sheath tumors in neurofibromatosis 1 patients. Furthermore, one DLCL lost CDKN2A from diagnosis to relapse. MDM2 overexpression was more frequent in aggressive than in indolent lymphomas, and in follicle center lymphomas none of our follicle center grade I/II lymphomas overexpressed MDM2. In contrast, MDM2 was overexpressed in 60% of grade III/diffuse follicle center lymphomas. Clinical correlations revealed novel and interesting findings. Both p53 disruption and low expression of E2F-1 correlated with poor response of aggressive lymphomas to treatment. Chemotherapeutic regimens used in lymphoma treatment are based on apoptosis induction, and as both E2F-1 and p53 are regulators of apoptosis, it is possible that the observed treatment failure is associated with reduced E2F-1- and p53-mediated apoptosis. Survival analyses revealed numerous novel and potentially important findings. Several of the studied cell cycle regulators carried independent prognostic value in various subsets of lymphomas. In DLCL, both p16INK4A inactivation and reduced E2F-1 expression conferred shortened survival. p53 alteration was associated with poor prognosis of both B-cell and, especially, T-cell lymphoma. Low expression of p27, a cell cycle regulator haplo-insufficient for tumor suppression, predicted poor outcome in indolent and aggressive lymphoma, and overexpression of cyclin D3 was associated with poor prognosis in indolent lymphomas. Finally, MDM2 overexpression identified among patients with follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell lymphomas cases with poor prognosis. While these results must necessarily be confirmed on larger prospective series of patients, the data nonetheless suggest that valuable prognostic information can be provided by studies of these cell cycle regulators.
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PMID:Molecular control of the cell cycle in cancer: biological and clinical aspects. 1281 37

The goal of this study was to determine whether a panel of tumor suppressor gene markers of allelic loss could serve as a representative indicator of gene damage and thereby provide further discriminative power over current staging systems for recurrence-free prognostication in patients undergoing liver transplantation in the presence of hepatocellular carcinoma. The paraffin blocks from 103 cases of hepatocellular carcinoma were obtained, and cellular targets were selected for tissue microdissection genotyping. Tumor suppressor gene loss was based on loss of heterozygosity situated within or adjacent to specific genes of interest (APC, CDKN2A, DCC, MET, MYC1, OGG1, p34, p53, PTEN). Microdissected tissue was amplified using polymerase chain reaction (PCR) with flanking oligonucleotides bearing fluorescent labels designed for GeneScan fragment analysis; PCR products were separated by capillary electrophoresis. Normal microdissected tissue samples for each case were evaluated for informative status with respect to individual alleles for 18 microsatellites at 10 genomic loci-1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, 17q, 18q. The measure of allelic loss of heterozygosity combined with tumor number, tumor size, vascular invasion, lobar distribution, and patient gender provide a highly discriminatory model for predicting cancer recurrence after liver transplantation. Using our previously developed artificial neural network model in combination with the genotyping results, unambiguous predictions were made for 91 of the103 patients (88.3%). Of these, 1 was lost to follow-up, and 9 died recurrence-free less than 3 years posttransplantation. For the remaining 81, the combined models predicted tumor recurrence outcomes with complete accuracy. Microdissection genotyping provides powerful supplementary discriminative information for tumor-free survival.
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PMID:Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. 1282 50

Hypermethylation of cytosines in CpG-rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 (p16(INK4a)/CDKN2A) and p14 (p14(ARF)) by methylation-specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco-related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3-22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9-17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex-smokers.
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PMID:Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. 1291 69

The multistep process of tumorigenesis has not been decoded to date, although numerous investigations into probable molecular changes have meanwhile been conducted. However, not only DNA changes or loss of alleles cause deregulation of gene function, but also epigenetic alterations (e.g. methylation) result in functional loss. The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14ARF and p16INK4a, which play active roles in the p53 and Rb tumor suppressive pathways. We therefore examined not only p16 and p14 proteins, but also alterations of the INK4a-ARF locus, including methylation and loss of heterozygosity in benign and malignant tumors of the head and neck (squamous cell carcinomas and pleomorphic adenomas). In benign pleomorphic adenomas, methylation of p14ARF was found in 1 out of 42 (2%) cases, whereas alterations of p16INK4a occurred in 12/42 (29%) pleomorphic adenomas. In HNSCC, methylation of p16INK4a occurred in 16 out of 50 (32%) carcinomas. P14ARF was found to be methylated in 8 out of 50 cases (16%). Our results demonstrate that alterations of the INK4a-ARF locus are frequent and important events not only in the carcinogenesis of malignant, but also in benign tumors.
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PMID:Genetic and epigenetic alterations of 9p21 gene products in benign and malignant tumors of the head and neck. 1292 39

Higher grade histological transformation of follicular lymphoma (FL) to more aggressive diffuse large B-cell lymphomas (DLBCL) occurs in 10-60% of the cases. Review of the current knowledge of genetic and molecular alterations associated with the higher grade transformation of FCL suggests that the process that leads to clinically and phenotypically similar end-point can occur by functionally diverse genetic lesions. The most commonly identified genetic alterations associated with the FCL transformation are TP53 gene mutations, inactivation of CDKN2A and CDKN2B genes and deregulation of the C-MYC gene. These lesions affect different aspects of normal cell physiology (apoptosis, cell cycle control, and proliferation) and are potential targets for gene-specific therapies.
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PMID:Higher grade transformation of follicular lymphoma: phenotypic tumor progression associated with diverse genetic lesions. 1295 50

Hepatocarcinogenesis may involve multiple mutations with distinctive pathogenetic and clinicopathologic significance. To test this hypothesis, 68 cases of hepatocellular carcinoma (HCC) were studied prospectively for genetic-clinicopathologic correlation. Ten pathologic characteristics were evaluated. TP53 (alias p53) gene mutation was studied by a polymerase chain reaction (PCR)-single-strand conformation polymorphism-sequencing; CDKN2B (alias p15) and CDKN2A (alias p16) gene methylation by methylation-specific PCR; and genetic imbalances by comparative genomic hybridization (CGH). TP53 gene mutations occurred in 25% of cases, more than half being codon 249 G to T transversion. Methylation of CDKN2A was frequent (61.7%); of CDKN2B, rare (5.9%). The CGH analysis showed a median of nine aberrations per case, with amplifications more frequent than deletions. Isochromosomes might be involved in about 25% of cases. Amplifications of 1q and 8q were most frequent. Clinicopathologic correlations showed that CDKN2A methylation was significantly associated with tumors arising in cirrhotic livers; amplifications of 17q was significant in multiple parameters of tumor invasiveness (size, venous invasion, poor cellular differentiation, microsatellite formation); other amplifications (1q, 6p, 10p, and 20p) were also significant in tumor invasion; and deletions (at 1p, 11q, 4q, and 14q) were significant in tumor growth. Consistent patterns of genetic alterations were defined in HCC, which might represent distinctive pathways in hepatocarcinogenesis.
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PMID:Clinicopathologic significance of genetic alterations in hepatocellular carcinoma. 1449 90

The UVB component of the solar spectrum induces DNA lesions that, in the absence of error-free DNA repair, may give rise during DNA replication to mutations in caretaker and gatekeeper genes. The DNA repair genes are the best candidates for caretaker genes as exemplified by the human hereditary xeroderma pigmentosum (XP) syndrome. Cultured XP cells are hypermutable after UVB irradiation. This increased mutation frequency is also found in gatekeeper genes, which govern signalling pathways implicated in the control of cellular proliferation, differentiation and survival of human epidermal keratinocytes. We describe and discuss the role of mutated gatekeeper genes in five specific signalling pathways which have been implicated in skin carcinogenesis. The pathways we focus on in this review are: (i) P16(INK4A)-CDK4/6-RB; (ii) P14(ARF)-HDM2-P53; (iii) Sonic hedgehog (SHH)/GLI; (iv) WNT/beta-catenin; and (v) Bone Morphogenetic Protein (BMP)/SMAD. 70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs). In XP cancers, the typically UVB-induced CC to TT tandem transitions represent approximately 60% of total mutations compared to 10-15% in skin tumours from DNA repair-proficient patients. Acquired activation of the pathways described herein can alter proliferation and differentiation of keratinocytes, allowing a damaged cell to replicate and give rise to mutated daughter cells, then eventually to the development of the carcinogenic process following clonal selection.
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PMID:UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis. 1452 Dec 17

Expression analysis of apoptotic genes was performed for 15 patients with acute myelocytic leukemia (AML) at the time of diagnosis to identify genes and signaling pathways involved in the regulation of cell survival and apoptosis during leukemogenesis. cDNA array analysis revealed 34 genes whose expression was significantly different compared to others. Tumor suppressor genes TP53 and CDKN2A were downregulated and protooncogenes JUN and GRB10 were upregulated. Furthermore, several cellular signaling pathways acting either in cell cycle regulation or in apoptosis were altered. Deregulation was found in pathways that contribute to genomic stability (by downregulation of either TP53 or CSE1L and by upregulation of GADD45A) and regulate cell cycle progression (by downregulation of CDKN2A and upregulation of RBBP4, CDC37, and NEDD5). Alterations at the transcriptional level were identified, namely, upregulation of JUN and E2F5. Abnormalities were observed in the regulation of the caspases through upregulation of CASP8 and by altered expression of BCL2-related pathway. Extrinsic apoptotic signals mediated by IGFs were deregulated and the glutathione detoxification pathway was downregulated. These findings provide insight into the regulation of balance between apoptosis and cell proliferation signals, and suggest that these genes and pathways may have an important role in the pathogenesis of AML.
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PMID:Changes in apoptosis-related pathways in acute myelocytic leukemia. 1455 42


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