UMLS:C0019829 - FACTA Search

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Query: UMLS:C0019829 (Hodgkin's disease)
30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P53 is a tumour suppressor gene, located in the short arm of chromosome 17, which encodes for a nuclear protein involved in the control of cellular growth, regulating the entry of the cell into the S-phase. P53 mutations have been identified in a progressively increasing number of human malignancies. Nuclear p53 protein is usually present in non-tumour cells in minute concentrations, due to its short half-life. In contrast, tumours with p53 mRNA mutations show a higher nuclear protein concentration, detectable by immunohistological techniques, due to stabilization by complexing with other proteins such as heat-shock protein or wild-type p53 protein. Levels of nuclear p53 protein detected by immunohistochemistry with the monoclonal antibody PAb 1801 were measured with the aid of an image analysis system in 83 non-Hodgkin's lymphomas (NHLs) and 13 cases of Hodgkin's disease, as well as in 14 cases of normal thymus, reactive tonsils, and lymphadenitis. High levels of p53 protein (greater than 5 per cent of the cells) were present only in high-grade lymphomas (in the proportion 13/55), with a peak incidence in Burkitt's lymphoma (5/8 cases). Lower levels (less than 5 per cent) of p53 protein were detected in low-grade B- and T-cell lymphomas, as well as in most of the cases of Hodgkin's disease, where p53 protein was selectively present in Hodgkin and Reed-Sternberg cells. In 5/14 reactive tonsils or lymph nodes, occasional p53-positive cells were identified. These results suggest a relationship between levels of p53 protein and the aggressiveness of NHL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:P53 protein expression in lymphomas and reactive lymphoid tissue. 138 24

Hodgkin's disease (HD) is characterized by the presence of the typical, clonal malignant Hodgkin and Reed-Sternberg (H-RS) cells in a hyperplastic background of normal reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils and stromal cells. The neoplastic nature of HD is based on aggressive clinical progression, presence of the proliferating and atypical H-RS cells, aneuploidy and cellular clonality. Immunophenotypical studies have demonstrated frequent expression of lymphoid "activation markers' including CD15, CD25, CD30, CD40, CD54, CD70, CD71, CD80, CD86 and MHC class II and less frequent expression of T- or B-cell-associated antigens by the neoplastic H-RS cells. The clonality of H-RS cells is demonstrated by clonal EBV integration, clonal cytogenetic abnormalities including p53 mutations and clonal immunoglobulin rearrangements in some HD cases. There is involvement of diverse molecules with oncogenic potential, including presence of viruses (Epstein-Barr virus and human herpes virus-6) and/or oncogenes/tumour suppressor genes (bcl-2/bcl-x, p53/MDM-2, c-myc, c-fms, N-ras, lck). The histopathological presentation and characteristic clinical features of HD correlate with an unbalanced production of multiple cytokines and define HD as a tumour of cytokine-producing cells. The proportion of malignant H-RS cells to reactive cellular components and fibrosis is dependent on the production of particular cytokines and allows subtyping of HD cases. The combined use of immunohistochemical, biochemical and molecular techniques has thus allowed recognition that HD represents more than one clinico-pathological entity with different types of H-RS cells. The defined mechanism for the biological nature, origin and oncogenesis of H-RS cells remains not fully understood, but is susceptible to further analysis using modern technology.
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PMID:Pathophysiology of Hodgkin's disease: functional and molecular aspects. 892 38

Mutations in the p53 tumour suppressor gene are the most common genetic alteration found in human cancers. Most of them are accompanied by stabilization of the protein, which renders it detectable through immunohistochemical techniques. Although p53 expression is a very common finding in Hodgkin's disease (HD), the status of the p53 gene is scarcely known, due to the difficulty in sequencing this gene in a lesion in which tumour cells are thought to constitute a very minor subpopulation, diluted in a background of supposedly benign cells. The pattern of expression of two downstream p53 proteins (MDM2 and p21 WAF1/CIP1, was studied as an indirect way of assessing p53 gene status. MDM2 is a wild-p53 inducible protein which may form a complex with p53, abrogating its function, as has been found in human sarcomas and other malignancies. p21WAF1/CIP1 is another protein inducible by wild-type p53, involved in inhibiting cell-cycle progression, through binding to cyclin/cyclin-dependent-kinase complexes. MDM2 and p21WAF1/CIP1 immunostaining was detected in all the cases analysed, independently of histological type, and were mainly present in Sternberg-Reed and Hodgkin (H & SR) cells. These immunohistochemical results were confirmed by Western blotting. To study the cause of MDM2 protein accumulation, MDM2 mRNA expression was also investigated by reverse transcription polymerase chain reaction (RT-PCR). The results show the presence of MDM2 transcripts in all cases of HD, albeit at lower levels than those found in reactive lymphoid tissue. These results seem to support the hypothesis that p53 is transcriptionally active in at least some of the H & SR cells in HD, and is able to induce MDM2 and p21WAF1/CIP1 protein expression.
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PMID:MDM2 and p21WAF1/CIP1, wild-type p53-induced proteins, are regularly expressed by Sternberg-Reed cells in Hodgkin's disease. 894 16

We have investigated the RB-1 tumour suppressor genes in a series of 20 non-Hodgkin's lymphomas (NHL). Polymerase chain reaction (PCR) amplification of polymorphic alleles indicated that there was evidence of allelic imbalance around 13q14, the site of the RB-1 gene, in at least 5 NHL. Immunohistochemical analysis of the RB-1 protein demonstrated wide variations in the percentage of cells exhibiting positive staining, but these usually correlated with differences in the proliferation index as indicated by staining of Ki67. Only 3/35 NHL exhibited significantly fewer cells expressing RB-1 protein than expressed Ki167. A comprehensive analysis of the mutation status of RB-1 in 20 NHL was carried out using PCR based strategies involving single strand conformational polymorphism (SSCP) gels. Most of the protein coding region was studied by analysing cDNA derived from its mRNA and the remaining 5'-end of the coding region investigated by analysing exon I of the gene. We also examined the promoter region of the gene. In none of the 20 NHL investigated were we able to identify a mutation: the only abnormal migrating fragment observed proved to be a polymorphism in exon I of the gene in 5 NHL. In one other case we detected instability at an intron repeat sequence, which had occurred during progression of the disease, but again no mutation of the protein coding region was found. The low levels of RB-1 protein expression that we had observed in a few of our NHL therefore did not appear to be due to mutation of the gene. These data suggest that mutation of RB-1 is not a common event in the evolution of NHL, but that there may be another, as yet unidentified, tumour suppressor gene near the RB-1 locus which is associated with NHL.
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PMID:Investigation of the RB-1 tumour suppressor gene in a United Kingdom series of non-Hodgkin's lymphomas. 903 Nov 17

p53 is a tumour suppressor gene which is often found to be inactivated in most types of human cancer. p53 is a transcription factor, the inactivation of which may lead to significant variations in the levels of p53 downstream proteins, such as p21WAF1/CIP1 and MDM2. In view of the significance of p21WAF1/CIP1 and MDM2 as wild-type (wt) p53 targets, this study was undertaken to monitor the varying expression of these proteins in non-Hodgkin's lymphomas (NHLs) in relation to p53 gene status. A total of 57 cases of different histological types of NHL were included in this study. Proteins p53, p21WAF1/CIP1, and MDM2 were analysed by immunohistochemical techniques, taking the levels expressed in reactive lymphoid tissues as reference points. p53 gene point mutations (exons 5-8) were looked for using the PCR-SSCP technique and direct sequencing. Fifteen of the 57 cases studied showed 16 mutations at the p53 gene: 12 missense, one nonsense, two silent mutations, and one frameshift deletion. Most missense mutations were associated with high levels of p53 protein, while the nonsense mutations and frameshift deletion did not induce detectable levels of p53. All cases with mutation at the p53 gene (15) showed null or low levels of p21WAF1/CIP1 and MDM2 proteins, suggesting that null or missense mutations at this gene give rise to a protein that is unable to transactivate the p21WAF1/CIP1 and MDM2 genes. The association between missense p53 mutation and dissociate immunophenotype (p53+, MDM2-, p21-) was statistically significant (Fisher's exact test, P = 0.0024). This anomalous p53+, MDM2-, p21- phenotype was also found in a small group of five cases with wt p53; this could indicate that in these cases p53 transactivation capacity has been abrogated by a mechanism other than p53 mutation. Most cases with the wt p53 gene show simultaneous immunohistochemical expression of all three proteins and often display higher levels than those found in reactive lymphoid tissue. There is a tendency for EBV-positive cases to harbour high levels of p53+ and p21+, suggesting that EBV could be involved in the nuclear accumulation of p53 and p21WAF1/CIP1 in NHL.
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PMID:p21WAF1/CIP1 and MDM2 expression in non-Hodgkin's lymphoma and their relationship to p53 status: a p53+, MDM2-, p21-immunophenotype associated with missense p53 mutations. 907 3

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
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PMID:Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. 928 6

Alteration of the tumour suppressor gene p53 is frequent in AIDS-related non-Hodgkin's lymphomas (AIDS-NHL), particularly in Burkitt's or Burkitt's-like lymphomas (BL/BLL). Since mechanisms of inactivation other than mutations have been advanced, the transcriptional activity of the p53 protein was studied in a functional assay in yeast in a series of AIDS-NHL lesions and compared with their morphology, immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP) analysis detection of other p53 abnormalities, Epstein-Barr virus (EBV) status, MDM-2 oncoprotein expression and c-MYC rearrangement. Polymorphic lymphoproliferations (PL), identified as precursors of NHL in HIV-patients, were also analysed in attempt to detect p53 modifications related to clonal progression. The functional assay detected p53 mutants in 40% (12/ 30) of the tumours: 50% (6/12) of BL/BLL, 40% (4/10) of diffuse large cell lymphomas (DLCL) and 25% (2/8) of PL. An oligoclonal or monoclonal population was identified in the two PL cases with mutant p53. An accumulation of the p53 protein was detected by IHC in 26% (8/30) of the tumours (five BL/BLL and three DLCL) and was associated with positive functional assay. In the 20 lesions tested by both of the screening methods for mutations, a p53 mutant pattern was detected in 55% of cases (11/20) and in 25% of cases (5/ 20) respectively with the functional assay and SSCP analysis of exons 5-8. There was no inverse correlation between the detection of EBV genome and the presence of p53 mutations and no overexpression of MDM-2 protein for the whole series. In conclusion, the functional assay was more sensitive than IHC and SSCP for the detection of p53 mutations in tumour samples. The mutations identified in AIDS-NHL lesions inactivate the p53 protein and in PL they could represent a selection of an aggressive clone.
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PMID:Functional analysis of the p53 protein in AIDS-related non-Hodgkin's lymphomas and polymorphic lymphoproliferations. 960 27

PTEN is a novel tumour suppressor gene that encodes a dual-specificity phosphatase with homology to adhesion molecules tensin and auxillin. It recently has been suggested that PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3, 4,5)P3], which mediates growth factor-induced activation of intracellular signalling, in particular through the serine-threonine kinase Akt, a known cell survival-promoting factor. PTEN has been mapped to 10q23.3, a region disrupted in several human tumours including haematological malignancies. We have analysed PTEN in a series of primary acute leukaemias and non-Hodgkin's lymphomas (NHLs) as well as in cell lines. We have also examined whether a correlation could be found between PTEN and Akt levels in these samples. We show here that the majority of cell lines studied carries PTEN abnormalities. At the structural level, we found mutations and hemizygous deletions in 40% of these cell lines, while a smaller number of primary haematological malignancies, in particular NHLs, carries PTEN mutations. Moreover, one-third of the cell lines had low PTEN transcript levels, and 60% of these samples had low or absent PTEN protein, which could not be attributed to gene silencing by hypermethylation. In addition, we found that PTEN and phosphorylated Akt levels are inversely correlated in the large majority of the examined samples. These findings suggest that PTEN plays a role in the pathogenesis of haematological malignancies and that it might be inactivated through a wider range of mechanisms than initially considered. The finding that PTEN levels inversely correlate with phosphorylated Akt supports the hypothesis that PTEN regulates PtdIns(3,4,5)P3and suggests a role for PTEN in apoptosis.
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PMID:PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. 993 26

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases, whereas p19ARF targets MDM2, a p53 inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways. To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-three (62%) tumours had alterations of one or more p53 pathway components (p53, p19ARF and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2. The lack of correlation between these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways.
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PMID:Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. 1008 36

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

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