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 t(11;14)(q13;q32) translocation, which juxtaposes the BCL1 oncogene with the Ig heavy chain locus, has been associated with an uncommon subtype of non-Hodgkin's lymphoma (NHL) termed mantle cell lymphoma (MCL). To date, no molecular marker that serves as an indicator of tumor progression or clinical prognosis has been described for NHLs with this translocation. We examined a panel of NHLs with t(11;14) for overexpression of p53 and correlated the results with single-strand conformation polymorphism (SSCP) analysis, karyotypic features, and clinical course. NHLs with t(11;14) were identified from 30 patients. The diagnosis was MCL for 23 of 30, small lymphocytic lymphoma for 4 of 30, and diffuse large-cell lymphoma for 3 of 30 cases. The results of immunohistochemistry analysis using a monoclonal anti-p53 antibody on paraffin-embedded specimens were compared with the SSCP data, the tumor karyotypes, and clinical course of each patient. DNA sequencing of exons was performed on cases that showed conformational changes by SSCP analysis. NHLs from 5 of 23 patients with MCL were positive for p53 overexpression. Deletions of chromosome 17p were identified in 2 of 30 cases, both of which were MCLs showing p53 overexpression. Two of the five MCLs with p53 overexpression showed evidence for TP53 mutations. None of the 18 MCLs negative for p53 overexpression showed conformational changes by SSCP. For these 18 patients with MCLs that did not overexpress p53, the median survival was 63 months, compared with 12 months for the 5 patients with MCLs positive for p53 overexpression (P < .001). These results suggest that p53 overexpression in MCL with t(11;14)(q13;q32) may serve as a marker of poor prognosis.
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PMID:p53 overexpression as a marker of poor prognosis in mantle cell lymphomas with t(11;14)(q13;q32). 757 80

Resection specimens from 83 patients with primary gastric lymphoma (PGL) of B cell phenotype at stage IE and at stage IIE according to the Ann Arbor classification were investigated. Histologically, these lymphomas could be divided into four types: Type I lesions (n = 24) were entirely made up of MALT lymphoma; Type II lesions (n = 13) were predominantly MALT lymphoma containing one to a few foci of high-grade B cell lymphoma; Type III lesions (n = 22) consisted largely of high-grade lymphoma with small areas of low-grade MALT lymphoma; and Type IV lesions (n = 24) were pure high-grade B cell lymphoma, mostly of the large cell type. All patients had undergone primary gastric resection, and 14 received additional chemotherapy (n = 12), or both chemotherapy and radiotherapy (n = 2). The survival probability was significantly higher for Types I and II lymphomas than for Types III and IV tumors (P < 0.05 by the generalized Wilcoxon test). According to The General Rules for the Gastric Cancer Study by the Japanese Research Society for Gastric Cancer, the stage of disease showed a clear distinction between each of them (P < 0.01 by the generalized Wilcoxon test). This staging method seemed to serve well as a prognostic indicator. The histological typing of the PGL of the present series also seemed to correlate with the gross appearance, pathologic stage and prognosis. Furthermore, the expression of cyclin D1, bcl-2 and p53 protein, and PCNA was immunohistochemically investigated in 42 cases of the present series. Most of the low-grade PGL (Types I and II) had less than 60% PCNA-positive cells, whereas the high-grade PGL (Types III and IV) had more than 60% positive cells. In a study for cyclin D1 protein, no cases showed the nuclear staining pattern characteristic for mantle cell lymphoma, and the cytoplasmic staining frequently observed in the node-based large B cell lymphoma was seldom identified in the PGL. This discrepancy might suggest a lineage difference among the morphologically similar, but site-different, lymphomas. On the other hand, bcl-2 protein overexpression was almost equal in frequency between the gastric and node-based high-grade B cell lymphomas. This is in contrast to the reports from Western countries, in which the majority of high-grade gastric tumors were bcl-2 negative.
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PMID:Clinicopathologic study of primary gastric lymphoma of B cell phenotype with special reference to low-grade B cell lymphoma of mucosa-associated lymphoid tissue among the Japanese. 858 Nov 46

Although p53 mutations have been described frequently in high-grade B-cell non-Hodgkin's lymphoma (NHL), they have only been reported occasionally in low-grade NHL. We therefore describe clincobiologic and molecular genetic findings in two patients with p53 mutations and leukemic mantle cell lymphoma featuring an unusually aggressive course. Circulating malignant cells showed irregularity of nuclear outline with frequent deep clefts in both cases. Immunologic studies of neoplastic cells from peripheral blood samples and from cells obtained from an involved lymph node showed a mantle B-cell phenotype (CD5+, CD19+, CD22+, CD23- or weakly+ and bright expression for surface immunoglobulins). Malignant cells were shown to be hyperdiploid by cytofluorimetric study of DNA content and the presence of the t(11;14)(q13q32) was documented in one case. An altered electrophoretic mobility of p53 exon 5 was seen in both cases, with a missense mutation at codon 158 present in one case and a CAG to TAG mutation resulting in a 167-stop codon present in the second case. The percent of reactive cells with the 1801 monoclonal antibody detecting an epitope of the p53 was 37% in one case and 1% in the second case, supporting the notion that immunologic overexpression cannot be used for a selection criterion for the detection of p53 mutations. From these findings and from data available in the literature the conclusion can be drawn that p53 gene mutations at codons 158 and 167 may be associated with lymphoproliferative disorders and that low- or intermediate-grade NHL, including leukemic mantle cell lymphoma, may frequently carry this genetic change.
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PMID:p53 exon 5 mutations in two cases of leukemic mantle cell lymphoma. 860 36

Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1/PRAD-1 gene overexpression. Some aggressive variants have been recognized with a blastic or large cell morphology, higher proliferative activity, and shorter survival. p53 gene mutations in lymphoid neoplasms have been detected mainly in high grade lymphomas and have been associated with tumor progression in follicular and small lymphocytic lymphomas. To determine the role of p53 alterations in MCL, we examined 35 typical and 8 aggressive variants (5 blastic and 3 large cell) of MCLs by a combination of immunohistochemistry, single-strand conformational polymorphism analysis of genomic DNA and/or cDNA obtained by reverse transcriptase-polymerase chain reaction, denaturing gradient gel electrophoresis, and sequencing. Of the 8 aggressive MCLs, 3 (38%) contained missense point mutations in axon 8 codon 278 (Pro --> Leu), exon 8 codon 273 Arg --> His), and exon 5 codon 151 (Pro --> Ser), respectively. A diffuse p53 protein overexpression was observed in more than 50% of the tumor cells in these 3 cases. A fourth blastic MCL also showed strong p53 immunoreactivity. However, no mutations were detected in exons 5-9 in this case. p53 expression was also detected in 10% of the cells in an additional large cell type of MCL and in less than 1% of the cells in 6 typical cases. No mutations were detected in any of these cases or in the remaining cases with no expression of the protein. Four nucleotide changes were observed by single-strand conformational polymorphism analysis in 4 typical MCLs with no overexpression of the protein. Direct sequencing showed that these nucleotide changes were located at exon 6 (1 case), intron 7 (2 cases), and intron 8 (1 case). The changes in exon 6 and intron 7 were known polymorphisms. The nucleotide change in intron 8 was outside splicing sites of the neighboring exons. The overall survival of the 3 patients with p53 mutations (median, 18.3 months) was significantly shorter than that of patients with the nonmutated MCLs (median, 49 months; P < .01). These findings indicate that p53 gene mutations are an infrequent phenomenon in MCLs and are associated with a subset of aggressive variants.
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PMID:p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. 860 52

Large-cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large-cell lymphoma related to MCL (L-MCL), and compare them to a group of classic small-cell MCL (s-MCL) cases. Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s-MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast-like cells (case 2-5). The median nuclear diameter, median nuclear area and proliferation index of L-MCLs and s-MCLs, were statistically different. Immunophenotypic characterization of four specimens of L-MCL and 10 of s-MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/-, CD5+, CD10-, CD23- phenotype in all cases except two (one CD5- and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L-MCLs and 5/10 s-MCLs demonstrated rearrangements of the bcl-1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L-MCLs and 1/9 s-MCLs had p53 mutations on single-strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl-2 by PCR or bcl-6 and c-myc by Southern blot. All patients with 'transformed' histology (versus 37% of all others) died of lymphoma; their survival (15-18 months; median 17) was much shorter than that of all the others (28-117+ months; median 43) (P=0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl-1 rearrangements did not have prognostic implications. This study documents the existence of large-cell variants of MCL and the poor prognosis associated with the 'transformed' cytologic type and/or p53 abnormalities.
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PMID:Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome. 863 52

Mutations of the p53 tumor suppressor gene have been described in several subtypes of non-Hodgkin's lymphoma, but the incidence of p53 mutations in mantle cell lymphoma (MCL) is unknown. We hypothesized that cases of MCL with a variant or high-grade cytology would have a higher likelihood of p53 mutations than typical MCL. We were also interested in the prognostic significance of p53 mutations in MCL. Therefore, a series of 53 well-characterized cases of MCL with DNA from 62 tissue samples were analyzed by the polymerase chain reaction with denaturing gradient gel electrophoresis for exons 5-8 of p53. Immunoperoxidase studies with the antibody DO-7 to p53 protein were also performed on frozen sections. We found mutations of the p53 gene in 8 of the 53 cases (15%) of MCL. Missense mutations predominated, and 50% of the mutations occurred at known p53 hotspot codons. Of 21 cases with variant cytology (ie, anaplastic or blastic), 6 (28.6%) had p53 mutations as compared with only 2 of 32 cases (6.3%) with typical MCL cytology (P = .05), and p53 mutations preceded the development of variant cytology in 2 patients. Overexpression of p53 protein was observed in 6 of the 8 cases (75%) with p53 mutations and in none of the 45 wild-type cases. The median survival of the cases with mutant p53 was only 1.3 years (all died), whereas the median survival of cases with germline p53 was 5.1 years (P = .023). These results suggest that mutations of p53 may be one mechanism involved in the development of variant forms of MCL and indicate that p53 mutations in MCL predict a poor prognosis.
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PMID:p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. 863 89

We report a unique case of mantle cell lymphoma in blastoid transformation associated with deletion of the long arm of chromosome 12 and with 90 kDa mdm-2 protein overexpression. Neither the mantle cells nor their blastoid counterparts expressed p53 gene product by immunohistochemical analysis. This seems to be the first reported case of this subtype of lymphoma associated with these specific cytogenetic and molecular genetic abnormalities.
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PMID:mdm-2 oncoprotein expression associated with deletion of the long arm of chromosome 12 in a case of mantle cell lymphoma with blastoid transformation [corrected]. 872 71

Loss-of-function mutations in the p53 tumor suppressor gene result in an altered response to DNA-damaging agents. Included in the mutant p53 phenotype are the loss of the G1 checkpoint and delayed apoptotic cell death, characteristics we have consistently observed in the AHH-1 tk+/- cell line following exposure to DNA-damaging agents. In order to determine the functional status of p53 in the AHH-1 tk+/- cell line, molecular analysis (single-strand conformational polymorphism [SSCP] and sequence analysis) was performed on exons 5-9 of the p53 gene. In addition, the status of the p53 gene in the closely related lymphoblast line, MCL-5, which, in our hands, has a much higher spontaneous rate of apoptosis than AHH-1 tk+/-, was also determined by molecular analysis. Initial SSCP analysis of AHH-1 tk+/- revealed an abnormal migration pattern of exon 8 when compared to a wild-type control. Subsequent sequence analysis indicated that a base-pair substitution (CGG-->TGG) mutation had occurred at codon 282, a reported "hot spot' for 5-methylcytosine mutations in the human p53 gene. Neither SSCP nor sequence analysis of exons 5-9 of MCL-5 indicated any differences from wild-type DNA. These results suggest that the lack of a G1 arrest and the delayed entrance into apoptosis observed in chemically-exposed AHH-1 tk+/- cells are, at least partially, accounted for by a loss-of-function mutation in the p53 gene.
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PMID:A mutation in the p53 tumor suppressor gene of AHH-1 tk+/- human lymphoblastoid cells. 884 77

Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1 gene overexpression. Some aggressive variants of MCL have been described with blastic or large cell morphology, higher proliferative activity, and shorter survival. The cyclin-dependent kinase inhibitors (CDKIs) p21Waf1 and p16INK4a have been suggested as candidates for tumor-suppressor genes. To determine the role of p21Waf1 and p16INK4a gene alterations in MCLs, we examined the expression, deletions, and mutations of these genes in a series of 24 MCLs, 18 typical, and 6 aggressive variants. Loss of expression and/or deletions of p21Waf1 and p16INK4a genes were detected in 4 (67%) aggressive MCLs but in none of the typical variants. Two aggressive MCLs showed a loss of p16INK4a expression. These cases showed homozygous deletions of p16INK4a gene by Southern blot analysis. An additional aggressive MCL in which expression could not be examined showed a hemizygous 9p12 deletion. Loss of p21Waf1 expression at both protein and mRNA levels was detected in an additional aggressive MCL. No p21Waf1 gene deletions or mutations were found in this case. The p21Waf1 expression in MCLs was independent of p53 mutations. The two cases with p53 mutations showed p21Waf1 and p16INK4a expression whereas the 4 aggressive MCLs with p16INK4a and p21Waf1 gene alterations had a wild-type p53. p21Waf1 and p16INK4a were expressed at mRNA and protein levels in all typical MCLs examined. No gene deletions or point mutations were found in typical variants. Two typical MCLs showed an anomalous single-stranded conformation polymorphism corresponding to the known polymorphisms at codon 148 of p16INK4a gene and codon 31 of p21Waf1 gene. These findings indicate that p21Waf1 and p16INK4a alterations are rare in typical MCLs but the loss of p21Waf1 and p16INK4a expression, and deletions of p16INK4a gene are associated with aggressive variants of MCLs, and they occur in a subset of tumors with a wild-type p53 gene.
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PMID:Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas. 897 1

Sixty-four cases of mantle cell (centrocytic) non-Hodgkin's lymphomas have been analyzed for their cytomorphologic features, proliferation indices, bcl-1 rearrangements, p53 expression patterns, and DNA content by both interphase cytogenetic and DNA flow cytometric analyses. According to cytomorphology, three subtypes were recognized: a common, a lymphoblastoid, and a pleomorphic variant of mantle cell lymphoma (MCL). Blastoid MCL subtypes were characterized by distinctly elevated mitotic counts (57 and 51/10 HPF v 21/10 high-power fields in common MCL), proliferation indices (58% and 53% v 27% in common types, respectively; P < .001), frequent bcl-1 rearrangements at the major translocation cluster locus (59% v 40%), and overexpression of p53 (21% v 6%). However, the most interesting finding was a striking tendency of blastoid MCL subtypes to harbor chromosome numbers in the tetraploid range (36% of lymphoblastoid and 80% of pleomorphic types v 8% of common variants, P < .001), a feature clearly separating these neoplasms from other types of B-cell non-Hodgkin's lymphoma and possibly being related to cyclin D1 overexpression. Our data indicate that, although characterized by a uniform immunophenotype and common biologic background, MCL shows a broad spectrum of morphologic features ranging from small cell to blastoid types and that the morphologic spectrum is mirrored by distinct biologic features.
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PMID:Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones. 902 66


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