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

p53 mutations are found in a variety of neoplasia. B-immunoblastic lymphoma (BIBL) is a rapidly progressive, aggressive lymphoma. As patients with acquired immunodeficiency syndrome (AIDS) live longer, BIBL is becoming an increasing problem. We asked three questions in our study. What is the frequency of p53 mutations in BIBL? Is it more frequent in patients with AIDS? Can immunohistochemical staining of lymph nodes for expression of p53 substitute for mutational analysis of p53 to detect lymphomas with mutated p53? Exons 5, 6, 7, 8 of the p53 gene (hot-spots for mutations) were amplified and examined for mutations by single-strand conformation polymorphism (SSCP) analysis. Altered migration was observed in 7 of 52 BIBL samples. Of these, 4 of 25 were from individuals infected with human immunodeficiency virus (HIV) and 3 of 27 were not infected with HIV. Direct sequencing of amplified material confirmed the presence of mutations in exons 5, 7, 8 of p53. A total of 26 BIBL as well as other lymphoma/leukemia samples, stained strongly by immunohistochemistry with three antibodies directed against human p53. Five of 6 BIBL samples with p53 mutations stained strongly for p53, but 20 lymphoma samples with no detectable p53 mutations also stained strongly for p53. Of note, however, 10 hyperplastic, nonmalignant lymph nodes from individuals either infected or not infected with HIV had negligible staining for p53 protein. In conclusion, p53 mutations occur in about 14% BIBL samples; the frequency of p53 mutations in BIBL in individuals with and without AIDS was similar. Positive p53 immunohistochemistry did not correlate with detectable p53 mutations in the same tissue, but positive immunohistochemical staining for p53 was only found in neoplastic lymph nodes. This latter finding provides a strong warning that p53 immunochemistry with available reagents cannot be used to determine which tumors have mutations of p53.
 ...
PMID:Mutation and protein expression of p53 in acquired immunodeficiency syndrome-related lymphomas. 833 55

Mutation of the p53 gene has been associated with treatment failure and poor outcome in various malignancies. It has been suggested that immunohistochemical analysis of p53 and p21Waf1, a downstream target, can be used to screen for p53 gene mutations. We determined the value of immunohistochemical screening for p53 gene mutations as a prognostic marker in a population-based group of B- and T-cell non-Hodgkin's lymphomas (NHLs). On the basis of p53 gene mutation status and immunohistochemically detected p53 and p21Waf1 expression in 34 lymphomas, we established an immunophenotype (delta p53) correlating with p53 gene mutation. The immunohistochemical analysis was extended to encompass 199 lymphomas from a population-based registry and was correlated with clinical parameters. Delta p53 showed 100% concordance with p53 gene mutation and was detected in 42 cases (21%). Multivariate analysis of advanced stage lymphomas showed that delta p53 was independently associated with treatment failure (relative risk, 3.8; P = 0.001). Delta p53 predicted poor survival when analyzing all patients (P = 0.0001), as well as B-cell (P = 0.04) and T-cell NHL (P = 0.000002). In multivariate analysis, delta p53 (relative risk, 2.2; P = 0.001) maintained prognostic significance. The impact on prognosis of delta p53 was highly significant in the low-intermediate-risk group (P = 0.00002). Comparing survival of the aggressive lymphoma patients in this group showed that the 8 delta p53 patients died within 1 year, whereas the median survival of the 28 non-delta p53 patients was 36 months. These results suggest that immunohistochemically assessed p53 status may predict treatment response and outcome in B- and T-cell NHL patients.
 ...
PMID:Disrupted p53 function as predictor of treatment failure and poor prognosis in B- and T-cell non-Hodgkin's lymphoma. 1035 42

The CHK2 gene encodes a protein kinase that is important for the regulation of cell cycle arrest after DNA damage. CHK2 acts downstream of ataxia teleangiecstasia mutated (ATM), modulates the function of p53 and may help mediate cell cycle arrest at G2/M by phosphorylation of Cdc25C. Recently, the human homolog of the checkpoint kinase Cds1 (CHK2) has been suggested to be a tumor suppressor gene. Heterozygous germline mutations have been reported in Li-Fraumeni syndrome (LFS), a highly penetrant familial cancer phenotype, and in sporadic colon cancer. LFS is associated with the development of lymphoid malignancies, especially childhood ALL. Therefore, we analyzed the DNA from 143 lymphoid malignancies to determine whether they had mutations of the CHK2 gene. The 14 exons of CHK2 were studied by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and sequencing of aberrantly migrating bands. One missense mutation changing serine to phenylalanine (codon 428) in an evolutionarily highly conserved domain was found in a non-Hodgkin's aggressive lymphoma. Another point mutation in the non-coding region was identified in one of adult T-cell leukemias (ATL) samples. This result suggests that mutation of the CHK2 gene may rarely be involved in the development of selected lymphomas.
 ...
PMID:Analysis of the CHK2 gene in lymphoid malignancies. 1169 18

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.
 ...
PMID:Molecular control of the cell cycle in cancer: biological and clinical aspects. 1281 37

The purpose of this study was to investigate the prognostic effects of four biological markers, BCL2, TP53, Ki-67, and P-glycoprotein, and their possible clinical relevance in addition to the international prognostic index (IPI) in diffuse large B-cell lymphoma (DLBCL). A total of 405 patients with aggressive lymphoma, stage II-IV, between 18 and 67 years, were randomized in a trial comparing CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). Of these, 267 cases were classified as DLBCL, with adequate paraffin blocks available in 207 cases, enabling immunohistochemical assessment of the expression of BCL2, TP53, P-glycoprotein, and Ki-67. In a multivariate analysis, stratified for IPI, high BCL2 expression (>10%) low (<60%) expression of Ki-67, and high TP53 protein expression (>75%) were shown to provide additional prognostic information with regard to overall or failure-free survival. We found no association between expression of P-glycoprotein and outcome. Assessment of BCL2 positivity might be introduced as part of the routine investigation in patients with DLBCL, but further studies are necessary to confirm the clinical relevance of Ki-67 and TP53 expression.
 ...
PMID:Assessment of biological prognostic factors provides clinically relevant information in patients with diffuse large B-cell lymphoma--a Nordic Lymphoma Group study. 1508 85

Progression of follicular lymphomas (FLs) is often accompanied by a spectrum of histologic changes and an aggressive clinical course. Although molecular alterations have been implicated in this event, the underlying factors are largely unknown. We studied the expression of selected tumor suppressor genes (P53 and retinoblastoma [RB]), oncogenes (MYC and BCL2), and a transferrin-receptor related protein (Trump) in sequential biopsies in 16 patients. Eleven patients progressed from grade I or II FL to aggressive B-cell lymphomas with diffuse morphology, whereas 5 patients presented with diffuse aggressive lymphomas and recurred with indolent lymphomas. Immunoreactivity for P53 correlated with higher histologic grade in lymphomas progressing from indolent to aggressive; however, only 1 patient who presented with aggressive lymphoma demonstrated a P53 gene mutation. Neither P53 immunoreactivity nor genotypic alterations correlated with presentation with an aggressive histology and relapse with FL. Growth fraction, as assessed by Ki-67 staining, and Trump expression correlated with histologic grade. Immunoreactivity for RB, BCL2, and MYC was seldom associated with progression. Eight of 9 cases tested exhibited identical immunoglobulin heavy and light chain rearrangements or identical BCL2 gene rearrangements in the sequential lymphomas. We conclude that P53 and Trump protein expression and proliferation activity correlate with histologic grade, but not with recurrence or progression of FL. Our results further indicate that progression of FL to diffuse aggressive lymphomas and presentation of an aggressive B-cell lymphoma followed by FL are clonally related.
 ...
PMID:Immunophenotypic and genotypic characterization of progression in follicular lymphomas. 1535 33

Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHR(b-1/d), responsive) mice were crossed with strain 129S1/SvIm (AHR(d/d), nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was responsive, an AHR-responsive phenotype in offspring increased mortality by 2-fold. In DBP-induced lymphomas, no evidence was found for TP53, beta-catenin, or Ki-ras mutations but lung adenomas of mice surviving to 10 months of age had mutations in Ki-ras codons 12 and 13. Lung adenomas exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice and raises the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults.
 ...
PMID:In utero exposure of mice to dibenzo[a,l]pyrene produces lymphoma in the offspring: role of the aryl hydrocarbon receptor. 1642 6

Richter's syndrome (RS) denotes the development of aggressive lymphoma that arises in patients with chronic lymphocytic leukemia (CLL). Presenting features typically include a rapid clinical deterioration with fever in the absence of infection, progressive lymph node enlargement, and an elevation in serum LDH. Diagnostic biopsy of affected sites usually reveals large cell lymphomas; however, Hodgkin variant cases have been described. Richter's transformation occurs in approx 5% of CLL patients and may be associated with infection with Epstein-Barr virus (EBV). Chromosome 11 and 14 abnormalities have also been described as well as tumor suppressor gene defects involving p53, p21, and p27. Treatment options for these patients are limited and include combination chemotherapy with or without the addition of monoclonal antibodies and stem cell transplantation. Response to therapy is variable and generally short-lived. Median survival is usually in the order of 5-8 mo. More effective management for RS is needed as well as prognostic models that will identify CLL patients at risk of transformation. This review will address the current status of RS and deal with the pathophysiology, diagnostic approach, and treatment of this challenging disease.
 ...
PMID:Recent advances in the diagnosis and therapy of Richter's syndrome. 1767 8

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 that may show a spectrum of morphological and phenotypic features broader than initially described. Although some patients may follow an indolent clinical evolution, in most of them the tumour has an aggressive behaviour with poor response to conventional chemotherapy. The genetic hallmark is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which is considered the initial oncogenic event. In addition to this translocation, MCL may carry a high number of secondary chromosomal and molecular alterations that target regulatory elements of the cell cycle machinery and senescence (BMI1/INK4/ARF/CDK4/RB1), DNA damage response pathways (ATM/CHK2/p53), and cell survival signals. The knowledge of these mechanisms and their influence on the behaviour of the tumour are facilitating the development of prognostic models with a more precise prediction of the clinical evolution of the patients. This information coupled with the availability of a new generation of innovative drugs targeting basic molecular process of the tumour cells, should facilitate the design of new therapeutic protocols able to overcome the resistance of this aggressive lymphoma to conventional treatments and improve the life expectancy of the patients.
 ...
PMID:Advances in the understanding of mantle cell lymphoma. 1841 Apr 53

Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). The clinical definition of RS is heterogeneous, and encompasses at least two biologically different conditions: (i) CLL transformation to a clonally related DLBCL, that accounts for the majority of cases; (ii) development of a DLBCL unrelated to the CLL clone. In clonally related RS, the pathogenetic link between the CLL and the DLBCL phases is substantiated by the acquisition of novel molecular lesions at the time of clinico-pathologic transformation. RS is not a rare event in the natural history of CLL, since the cumulative incidence of RS at 10 years exceeds 10%. Prompt recognition of RS is known to be clinically useful, and may be favoured by close monitoring of CLL patients harbouring clinical and/or biological risk factors of RS development. Conventional risk factors that are independent predictors of RS development at the time of CLL diagnosis include: (i) expression of CD38; (ii) absence of del13q14 and (iii) lymph node size > or =3 cm. Other risk factors of RS development include CD38 genotype and usage of specific immunoglobulin variable genes. The molecular pathogenesis of RS has been elucidated to a certain extent. Acquisition of TP53 mutations and/or 17p13 deletion is a frequent molecular event in RS, as it is in other types of transformation from indolent to aggressive B-cell malignancies. Additional molecular alterations are being revealed by genome wide studies. Once that transformation has occurred, RS prognosis may be predicted by the RS score, based on performance status, LDH, platelet count, tumour size and number of prior therapies. Depending on patient's age and RS score, the therapeutic options for RS may range from conventional immunochemotherapy to allogeneic bone marrow transplantation.
 ...
PMID:Richter syndrome: molecular insights and clinical perspectives. 1920 12


1 2 3 4 Next >>