Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most common tumour suppressor gene altered in human cancers is p53, which is located on the short arm of chromosome 17. Structural abnormalities of the short arm and loss of chromosome 17 have been reported to confer resistance to chemotherapy in patients with non-Hodgkin's lymphoma (NHL). Therefore we studied the incidence and prognostic value of p53 deletions in patients with NHL by fluorescence in-situ hybridization using a 40 kb cosmid probe. Specimens obtained from 79 patients with NHL were studied. 46 patients were untreated, and 33 were previously treated. 40 tumours had indolent and 39 had aggressive histologies. p53 deletions were observed in 14 specimens (18%) in 32-90% of the cells. No statistically significant difference in the incidence of p53 deletion was observed between indolent and aggressive NHLs or between untreated and previously treated patients. However, p53 deletions were observed in three of four patients with transformed lymphoma. In the untreated patients, p53 deletion had no effect on response to therapy, time to treatment failure, or survival. We conclude that p53 deletions are uncommon in NHL, and may be frequent in patients with transformed lymphoma. In this study, p53 deletions did not influence treatment outcome or prognosis of NHL. Because monosomy 17 and 17p abnormalities have been reported to confer poor prognosis in NHL, other tumour suppressor genes on 17p should therefore be studied.
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PMID:Analysis of p53 gene deletions in patients with non-Hodgkin's lymphoma by dual-colour fluorescence in-situ hybridization. 932 89

Microsatellites are unique highly polymorphic and informative genetic markers dispersed in the human genome. Their detection by PCR is rapid and a wide variety of DNA sources including archival material are available for diagnostic purposes. Microsatellite typing of haematological neoplasms may be applied to the search for loss of heterozygosity at loci possibly harbouring tumour suppressor genes, for example in acute lymphoblastic leukaemia. The technique may detect submicroscopical chromosomal deletions which are not visible in the leukaemic karyotype. RER+ tumours exhibiting microsatellite instability appear to be rare among haematological cancers with the possible exception of lymphoid tumours in immunosuppressed patients and lymphomas derived from mucosa-associated lymphoid tissue. An X-chromosomal microsatellite near the human androgen receptor gene (HUMARA) may be used for clonal X-inactivation analysis. Microsatellites therefore represent a collection of powerful genetic markers suitable to tackle questions relevant to basic research and clinical problems in leukaemia and lymphoma.
Leuk Lymphoma 1997 Dec
PMID:Microsatellite markers in leukaemia and lymphoma: comments on a timely topic. 949 99

The polymerase chain reaction (PCR) offers a practical means of studying the molecular genetic features of lymphomas. The method is rapid and, as formalin-fixed, paraffin processed samples can be used, does not require special tissue handling procedures. PCR amplified immunoglobulin and T cell receptor gene rearrangements can be exploited as markers of clonality and lineage and genetic abnormalities such as chromosome translocations and mutations of oncogenes and tumour suppressor genes can be used to identify specific lymphoma types. Polymorphic X linked loci may also be used as markers of clonality in females. Direct sequencing of PCR amplified IGH variable regions has provided insights into the developmental stages, susceptibility to antigen drive and dissemination patterns of lymphomas. The role of oncogenes and tumour suppressor genes such as MYC and TP53 in lymphomas can be studied by PCR amplification of mutation hotspots and direct sequencing of products. Known viral and bacterial DNA can readily be identified using PCR and unknown organisms sought using conserved primers to amplify polymorphic sequences. PCR analysis of the lymphomas and related disorders has accelerated our understanding of their molecular biology and provides a practical tool with diagnostic and prognostic applications. Future development of in situ PCR methods will provide cellular localization of genetic defects and infectious agents.
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PMID:Polymerase chain reaction in the assessment of lymphomas. 954 84

The evolution of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multi-stage process, comprising the sequential development of chronic H. pylori-associated gastritis, low grade and high grade lymphoma. The genesis of MALT lymphoma embodies the mechanisms of both physiological immune responses and the acquisition of genetic abnormalities. The tumour probably originates from an autoreactive MALT marginal zone B cell, which is generated during H. pylori infection. As a consequence of a genotoxic insult induced by H. pylori infection, the progenitor tumour cell may become genetically unstable and develop genetic abnormalities such as the t(11;18) translocation, trisomy three, c-myc and p53 mutations during a phase of expansion, which lead to partial transformation. With the growth help from H. pylori specific T cells, this abnormal B cell clone may undergo clonal expansion and gradually form a low grade MALT lymphoma. Additional genetic abnormalities including the t(1;14) translocation and other uncharacterised events could completely transform this abnormal B cell clone and result in escape from T cell dependency. Finally, further genetic events such as complete inactivation of the tumour suppressor genes p53 and p16, and possible activation of c-myc oncogene by translocation or other undetermined abnormalities can result in high grade transformation
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PMID:Recent advances in our understanding of the biology and pathogenesis of gastric mucosa-associated lymphoid tissue (malt) lymphoma. 966 52

The NF-kappaB/Rel family of transcription factors regulates a wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-kappaB/Rel proteins and their IkappaB regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-kappaB/Rel/IkappaB signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed-Sternberg (H/RS) cells in a reactive background of non-neoplastic cells. The peculiar activated phenotype of Hodgkin and Reed-Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-kappaB transcription factor. Here, we report the detection of mutations of the IkBa gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkin's disease. The presence of defective IkappaBalpha is thus likely to explain the constitutive activation of NF-kappaB in these cells and suggests that IkappaBalpha is a tumour suppressor controlling the oncogenic activation of NF-kappaB in Hodgkin and Reed-Sternberg cells.
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PMID:Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. 1034 Mar 77

A Task Group of the ICRP Committee 1 (Radiation Effects) has reviewed relevant data with the objective of advising the Main Commission of the ICRP on the possible implications for radiological protection of emerging views on genetic susceptibility to cancer (Chapter 1). Chapter 2 considers DNA damage and its processing/repair after ionising radiation and serves principally to demonstrate that a few rare cancer-prone, human recessive genetic disorders show DNA repair deficiency and profound increases in radiosensitivity. Less dramatic changes in radiosensitivity are also apparent in a wider range of such disorders. The cellular mechanisms that underly the association between DNA damage processing and tumorigenesis are discussed. Chapter 3 reviews the mechanisms and genetics of solid tumours illustrating the ways in which mutations in proto-oncogenes, tumour suppressor genes together with those in DNA repair and cell cycle control genes can contribute to tumour development. Specific examples are given of how germ line mutation of such genes can predispose to familial cancer. It is judged that up to 5% of all solid tumours have a recognisable genetic component. Heritable organ-specific effects are most usual and cancers of the breast and colon tend to show the most obvious genetic components. Clearly discernible genetic effects are seen when rare dominant germ line mutations express strongly as familial cancer (high penetrance mutations), but the existence of perhaps less rare low penetrance mutations and gene-gene interactions are recognised but not well understood. Chapter 4 considers the mechanisms and genetics of lympho-haemopoietic tumours. Specific chromosomal translocations and proto-oncogene activation events are much more frequent in human leukaemia/lymphoma than in solid tumours. Genetic predisposition to leukaemia/lymphoma is found in a number of non-familial recessive genetic disorders of DNA processing and/or chromosomal instability. Familial manifestation of susceptibility to these tumours is, however, extremely rare. The genetic component, although poorly defined, is judged to be less than that of solid tumours and expressed largely in childhood. Chapter 5 reviews and discusses limited data that comment upon tumorigenic radiosensitivity in cancer-prone genetic conditions. From knowledge of the fundamental processes involved it is judged that in most, but not all, cases genetic susceptibility to spontaneous tumours will be accompanied by a greater-than-normal risk after radiation. A review of epidemiological, clinical and experimental data relevant to this issue suggests that although a wide range of different sensitivities may be involved, a factor of 10 increase in sensitivity broadly accords with the limited human data available. This interim judgement of a factor of 10 increase in radiation risk in such human genetic disorders is made for the purposes of illustrative modelling and calculation. In addition, specific attention is given to breast cancer risk in heterozygotes for the radiosensitive human disorder, ataxia-telangiectasia; this association, while in no way discounted, is judged to be less strong than that claimed by some. Chapter 6 discusses and develops computational modelling procedures that aim to describe the impact of genetic factors on radiation-tumorigenesis in human populations. Estimates of the prevalence of known cancer-prone genetic disorders are made but breast cancer susceptibility is used to illustrate the application of the model developed. The most important message to emerge from this work is that, even at an assumed high level of radiation sensitivity, the prevalence of familial (high penetrance) genetic disorders in the population is too low (<1%) for there to be a significant impact on risk in typical human populations. In principle, however, there is the potential for such impact in atypical inbred sub-populations where these mutations can be more common. (ABSTRACT TRUNCATED)
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PMID:Genetic susceptibility to cancer. ICRP publication 79. Approved by the Commission in May 1997. International Commission on Radiological Protection. 1040 27

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.
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PMID:Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). 1055 88

Productive rearrangement of the T-cell receptor (TCR) beta gene and signalling through the pre-TCR-CD3 complex are required for survival, proliferation and differentiation of T-cell progenitors (pro-T cells). Here we identify a role for death receptor signalling in early T-cell development using a dominant-negative mutant of the death receptor signal transducer FADD/MORT1 (FADD-DN). In rag-1(-/-) thymocytes, which are defective in antigen receptor gene rearrangement, FADD-DN bypassed the requirement for pre-TCR signalling, promoting pro-T-cell survival and differentiation to the more mature pre-T stage. Surprisingly, differentiation was not accompanied by the proliferation that occurs normally during transition to the pre-T stage. Consistent with a role for FADD/MORT1 in this cell division, FADD-DN rag-1(-/-) pro-T cells failed to proliferate in response to CD3epsilon ligation. Concomitant signalling through the pre-TCR and death receptors appears to trigger pro-T cell survival, proliferation and differentiation, whereas death receptor signalling in thymocytes that lack a pre-TCR induces apoptosis. Later in life all FADD-DN rag-1(-/-) mice developed thymic lymphoma, indicating that FADD/MORT1 can act as a tumour suppressor.
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PMID:FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. 1069 35

Cancer chemoprevention uses natural- or synthetic chemical compounds to reverse, suppress or to prevent one or more of the biological events leading to the development of cancer. Chemopreventive agents are classified as blocking or suppressing according to their action on either the initiation or promotion-progression phases in experimental models using carcinogen treated animals. Transgenic animal technology has resulted in a plethora of murine models for cancer research providing insight into the complex oncogenic events contributing to the loss of cell cycle control and tumourigenesis. Transgenic models also offer an important opportunity to identify and study both tumourigens and chemopreventive agents. However, so far chemoprevention has in such models only been investigated to a limited degree and primarily in models with inactivated tumour suppressor genes. Studies show that spontaneous tumour developing due to loss of p53 function may be offset by preventive measures. The preventive actions of retinoids and polyamine synthesis inhibitors have been studied in the PIM mouse susceptible to lymphoma development. Most chemopreventive studies have been performed on murine familial adenomatous polyposis (FAP) models, which carry one non-functional apc gene and develop multiple intestinal adenomas upon inactivation of the wild type allele. Particularly non-steroidal anti-inflammatory drugs NSAIDs, which block COX-2, but also food components such as n-3 fatty acids show promising chemopreventive effects in these models. Transgenic cancer models demonstrate a strong gene-environment interaction, which is promising for the development of chemopreventive strategies.
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PMID:Use of transgenic mice in identifying chemopreventive agents. 1072 Jul 73

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.
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PMID:Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A. 1080 23


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