Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bcl-2 oncogene plays an important role in carcinogenesis by inhibiting cell death (apoptosis). It was initially discovered in follicular B cell lymphoma with t(14,18) and subsequently found in other malignant and premalignant lesions. Alteration of the normal controls of cell proliferation is also a significant factor in the multistep process of tumorigenesis. The proliferative activity of a given lesion is commonly evaluated by MIB 1, a monoclonal antibody to Ki67 proliferation antigen. Mutation of the p53 gene is considered the most common genetic aberration in colorectal cancer. Immunohistochemical (IHC) staining expression of bcl-2, Ki67, and p53 was retrospectively investigated in a series of 52 colorectal carcinomas and 56 adenomas. The aim of the study was twofold: (i) to investigate any correlation between MIB 1, p53, and bcl-2 immunostaining expression in colonic adenomas and carcinomas and (ii) to identify any relation between these markers and several histopathologic parameters including tumor size, pathologic stage, lymph node metastasis, angiolymphatic invasion, tumor grade, and differentiation in colon carcinomas. bcl-2 was consistently higher in adenomas than in carcinomas. There were 44 of 56 (78.6%) adenomas and 27 of 52 (51.9%) carcinomas positive for bcl-2 (P = 0.004). The mean Ki67 labeling index (LI) was 30.05 +/- 7.6 and 38.12 +/- 11.01 in adenomas and carcinomas, respectively (P = 0.0001). p53 was significantly higher in carcinomas (35 of 52 [67.3%]) than in adenomas (18 of 56 [32.1%]) (P = 0.0004). Expression of bcl-2 in carcinoma was associated with a lower p53 levels and lower mean Ki67 LI and with favorable histopathologic parameters. Higher p53 and Ki67 values were associated with prognostically poor histopathologic features (differentiation and Duke's stage). We conclude that, in contrast to p53 and Ki67, bcl-2 oncoprotein expression is probably an early step in the process of colon carcinogenesis, and its expression may be associated with favorable pathologic parameters. Furthermore, an inverse relation exists between p53 and Ki67, and bcl-2 IHC expression in colonic neoplasia. Evaluation of bcl-2, p53, and Ki67 IHC expression in colonic carcinoma may be of value in predicting the clinical course in these patients.
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PMID:Immunohistochemical expression of bcl-2 and p53 oncoproteins: correlation with Ki67 proliferation index and prognostic histopathologic parameters in colorectal neoplasia. 1098 68

The molecular basis accounting for the peculiar clinical and biological features of hairy cell leukaemia (HCL) is currently unknown. Deregulation of cell cycle genes plays a significant role in oncogenesis and there is considerable evidence suggesting that Cdk inhibitors (Ckis) function as tumour suppressors. We and others have recently demonstrated low expression of Cki p27 in very aggressive neoplasms and high-grade lymphomas. To investigate whether HCL cases express normal p27 protein, as in other low-grade lymphomas with a low proliferation index, 58 cases of HCL were characterized using a sensitive biotin-streptavidin-immunoperoxidase technique and specific antibodies against p27. All HCL cases showed either no or very weak reactivity, in contrast to other types of low-grade B-cell lymphoma [22 cases of chronic lymphocytic leukaemia (CLL), 12 cases of gastric marginal B-cell lymphoma (MALT), 16 cases of follicular lymphomas and two cases of splenic marginal zone lymphomas]. To investigate the possible mechanism(s) accounting for the low p27 expression observed in hairy cells, multiple approaches were used. According to these molecular studies, low levels of p2 7 are not as a result of (1) increased ubiquitin-mediated degradation, (2) decreased levels of p27 transcription or (3) p27 somatic mutations and/or allelic loss. These findings suggest that low p27 protein expression in HCL may be achieved through post-transcriptional regulation. Finally, our data demonstrate that p27 expression in HCL does not correlate with either cell cycle progression or proliferation index, suggesting that low levels of p27 in hairy cells may be associated with their unique stage of B-cell differentiation and/or the activation of as yet unknown pathways.
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PMID:Low expression of p27 and low proliferation index do not correlate in hairy cell leukaemia. 1109 Dec 10

The recently identified decoy receptor 3 (DcR3) binds to FasL and inhibits FasL-induced apoptosis, and is considered to play a role in the immune escape system of neoplastic cells. To examine the involvement of DcR3 in the immune evasions of virus-associated lymphoma, we analyzed the amplification and expression of DcR3, using dot blot and in situ hybridization (ISH), in 45 cases, which included 17 cases with Epstein-Barr virus (EBV)-associated lymphoma (seven pyothorax-associated B-cell lymphomas (PAL); ten natural killer lymphoma (NKL)), seven cases with adult T-cell leukemia lymphoma (ATLL), 13 Hodgkin's disease (eight EBV-associated cases; five non-EBV-associated cases), and eight control cases (three reactive lymphadenopathy; five non-EBV-associated-B-cell lymphoma). EBV-associated PAL and NKL exhibited DcR3 amplification and expression in lymphoma cells. ATLL also showed DcR3 expression and amplification. The cases with DcR3 amplification showed DcR3 expression; however, the expression was confined in the neoplastic cells, but not in the reactive cells. In Hodgkin's disease (HD), DcR3 was expressed only in Hodgkin and Reed-Sternberg giant (H-RS) cells. However, DcR3 was not expressed or amplified in reactive lymphadenopathy. Non-EBV-associated B-cell lymphoma also rarely expressed DcR3, and showed no amplification except in two cases, in which rare expression was present. Our results suggest that EBV and HTLV-I probably use DcR3 to escape from the immune system during lymphomagenesis, or virus-infected lymphoma cells with DcR3 expression might be selected in the multistep tumorigenesis.
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PMID:Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas. 1109 89

To elucidate the role of p53/p16(INK4a)/RB1 pathways in the tumorigenesis of primary central nervous system lymphomas (PCNSLs), we have analyzed p14(ARF), p16(INK4a), RB1, p21(Waf1), and p27(Kip1) status in a series of their 18 sporadic cases of diffuse large B-cell lymphoma, using methylation-specific PCR, differential PCR, and immunohistochemistry. Homozygous deletion or methylation of p14(ARF) was detected in 10 (56%) PCNSLs, and they were almost entirely deletions (except 1 case). A total of 11 (61%) PCNSLs demonstrated homozygous deletion (6 cases) or methylation (5 cases) of p16(INK4a). Six tumors showed both p14(ARF) and p16(INK4a) homozygous deletions. Hypermethylation of the RB1 and the p27(Kip1) promoter region was detected in 2 (11%) cases, whereas p21(Waf1) methylation was not detected in any. Immunohistochemistry revealed loss of p14(ARF) and p16(INK4a) expression in 10 (56%) samples, correlating with the gene status. Four cases showed independent negative immunoreactivity for pRB and p27(Kip1), and nearly one-half of cases (8 of 18; 44%) were characterized by lack of p21(Waf1) expression. These results indicate that inactivation of p14(ARF) and p16(INK4a) by either homozygous deletion or promoter hypermethylation represents an important molecular pathogenesis in PCNSLs. Hypermethylation of RB1, p21(Waf1), and p27(Kip1) appears to be of minor significance, these genes being independently methylated in PCNSLs.
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PMID:Frequent alterations of the p14(ARF) and p16(INK4a) genes in primary central nervous system lymphomas. 1152 21

The association of systemic lupus erythematosus (SLE) and B-cell malignancy is widely reported in the literature. Here we report nine cases of concurrent of SLE or discoid lupus erythematosus (DLE) and lymphoma or plasma cell disorder. A MEDLINE search was done using the keywords, 'SLE' and 'lymphoma' and the characteristics of all identified cases were summarized and analyzed, along with data from our own cases. Numerous variants of B-cell malignancies were encountered in these patients. B-cell malignancy occurs after the diagnosis and treatment of SLE in most reported cases, although it may precede SLE, or occur synchronously with it. The age at onset of the B-cell neoplasm in SLE patients is similar to that in the general population. Mortality in patients with both diseases is associated with progressive B-cell neoplasm, sepsis secondary to either disease, or both. B-cell malignancy and SLE seem to run independent clinical courses rather than being affected by each other. The use of immunosuppressive drugs is common in patients with SLE diagnosed prior to B-cell lymphoma, arguing that the effect of immunosuppression on the pathogenesis of lymphoma can not be excluded. Three areas worthy of study regarding the probable mechanisms for the occurrence of SLE and B-cell malignancies are discussed. A tumor suppressor gene PTEN may link the two disorders via a defective apoptosis pathway to eliminate hyperactive B and T cells in SLE. The accumulation of clonally expanded hyperactive B-cells that recognize self-antigens in the lymph nodes of SLE may predispose these B-cells to DNA breaks, facilitating tumorigenesis. Lastly, EBV infection, found to have a high prevalence in SLE patients, may serve as a common etiological factor in both disorders.
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PMID:Systemic lupus erythematosus and B-cell hematologic neoplasm. 1178 71

The bcl-x gene product has two forms, bcl-xl and bcl-xs. The bcl-xl form, similar to bcl-2, inhibits apoptosis. Reverse transcriptase-polymerase chain reaction/single-stranded conformation polymorphism (RT-PCR-SSCP) gel analysis was used to screen for mutations of the bcl-xl transcript of 50 non-Hodgkin's lymphoma (NHL) cases. One missense mutation in a patient with diffuse large B-cell lymphoma was found. Sequence analysis of this case showed that AGC (Ser) was mutated to GGC (Gly) in codon 154. An examination of mutation and/or polymorphism in born marrow samples of this case and 50 normal controls by the RT-PCR-SSCP method could not detect bandshifts. Mutation of the bcl-x gene in NHL has not been reported previously. There is a possibility that mutation of the bcl-x gene play a role in the tumorigenesis of NHL.
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PMID:Mutation of bcl-x gene in non-Hodgkin's lymphoma. 1183 37

We analyzed the role of 4 genes, TCL-1, MTCP-1, TML-1 and ATM, in the early pathogenesis of T cell leukemia, with particular interest in the characteristics of long-standing non-leukemic clonal proliferations in ataxia-telangiectasia (A-T) patients. Five patients were studied: 4 patients had A-T (2 of whom had non-leukemic clonal proliferations [ATCP]), 1 had B cell lymphoma and 1 had T-ALL; a fifth patient with T-PLL did not have A-T. We measured the levels of expression for TCL-1, MTCP-1 and TML-1. TCL-1, not expressed in unstimulated mature T cells, was upregulated in the peripheral blood leukocytes (PBL) of the 2 A-T patients with ATCP. It was also expressed in the malignant cells of the A-T patient with B cell lymphoma and the T-PLL cells of the patient without A-T. In the same cells, MTCP-1 type A was expressed equally in all 5 patients, as well as in the controls; MTCP-1 type B transcripts were not observed. TML-1, also not expressed in unstimulated T cells, was expressed in the PBL of one A-T patient with ATCP and in the leukemic cells of the non-A-T T-PLL patient. These expression patterns were compared to cellular immunophenotypes. The non-leukemic clonal T cell populations had the characteristics of immature T cells. We conclude that TCL-1 and TML-1 play a role in cell proliferation and survival but are not pivotal genes in the progression to malignancy, even when the ATM gene is mutated. Additional genetic alterations must occur to initiate tumorigenesis.
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PMID:TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal proliferations associated with ataxia-telangiectasia. 1185 46

A rare subset of HIV lymphoma, known as primary effusion lymphoma (PEL), is a high-grade tumour carrying human herpes virus 8 (HHV-8). Very little is known about genomic aberration in PEL, and only a few HIV-negative PEL have been reported. Here we report the results of chromosomal analysis and comparative genomic hybridisation (CGH) conducted to detect regions of gain and loss, in five HIV-negative Japanese cases of HHV-8-negative PEL. All patients except one (35-year-old female) were elderly men and the morphologic examination showed large cell type. PEL expressed B-cell-associated and activation-associated antigens, and exhibited clonal immunoglobulin genes. No HHV-8 was detected in all four examined cases, but Epstein-Barr virus (EBV) was detected in one case. Genomic abnormalities and aberrations were identified in all HHV-8/HIV-negative PEL. CGH studies showed gain in 19 of 24 chromosomes. Gains of 3q13-27, 8q24, 10q21-23 and Yq were detected in two of the five cases, but other gains were noted in each case. Chromosomal analysis revealed complex abnormalities both in numbers and structures. Burkitt lymphoma-associated t(8;22) was detected in one case, but +8 chromosome and c-myc amplification were detected in the other three cases by Southern blot and/or fluorecence in situ hybridization (FISH). Abnormality of chromosome 8, which associates with c-myc, was detected in four of the five HHV-8/HIV-negative PEL. However, the other common genomic abnormalities of HHV-8/HIV-negative PEL were not detected in our study, but the complex abnormalities seemed to be true rather than the usual large B-cell lymphoma. Our results suggest that multi-step genomic abnormalities might be associated in HHV-8/HIV-negative PEL tumorigenesis.
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PMID:Chromosomal and comparative genomic analyses of HHV-8-negative primary effusion lymphoma in five HIV-negative Japanese patients. 1200 64

The relationship between Epstein Barr Virus (EBV) and the human host is commonly benign, whereas the development of malignancy is most likely due to imbalance between the virus and host's immune system. The aim of this study was to analyze the association of EBV with pediatric lymphomas in human immunodeficiency virus (HIV) patients. Four consecutive patients with a histological and clinical diagnosis of lymphomas among 351 pediatric HIV-infected children prospectively followed up at our hospital since 1991 were studied. The cases included one diffuse fibrosis lymphocyte depletion subtype Hodgkin's lymphoma, 2 Burkitt's lymphomas, and one primary diffuse large B-cell lymphoma of the central nervous system. We assessed EBV presence by LMP-1 protein labeling by immunohistochemistry and in situ hybridization for EBERs in formalin-fixed and paraffin-embedded biopsies from all four cases. All HIV-associated lymphomas studied were found to be associated with EBV. The lymphoproliferative action of EBV may induce oncogenesis by increasing the probability of genetic alterations and/or by expanding an already malignant clone. As an oncogenic protein, LMP-1 expression by tumor cells supports the involvement of EBV in disease pathogenesis.
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PMID:Epstein Barr virus-associated lymphoma in HIV-infected children. 1209 68

Somatic hypermutation (SHM), coupled to selection by antigen, generates high-affinity antibodies during germinal center (GC) B cell maturation. SHM is known to affect Bcl6, four additional oncogenes in diffuse large B cell lymphoma, and the CD95Fas gene and is regarded as a major mechanism of B cell tumorigenesis. We find that mutations in the genes encoding the B cell receptor (BCR) accessory proteins B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a) occur as often as Ig genes in a broad spectrum of GC- and post-GC-derived malignant B cell lines, as well as in normal peripheral B cells. These B29 and mb1 mutations are typical SHM consisting largely of single nucleotide substitutions targeted to hotspots. The B29 and mb1 mutations appear at frequencies similar to those of other non-Ig genes but lower than Ig genes. The distribution of mb1 mutations followed the characteristic pattern found in Ig and most non-Ig genes. In contrast, B29 mutations displayed a bimodal distribution resembling the CD95Fas gene, in which promoter distal mutations conferred resistance to apoptosis. Distal B29 mutations in the cytoplasmic domain may contribute to B cell survival by limiting BCR signaling. B29 and mb1 are mutated in a much broader spectrum of GC-derived B cells than any other known somatically hypermutated non-Ig gene. This may be caused by the common cis-acting regulatory sequences that control the requisite coexpression of the B29, mb1, and Ig chains in the BCR.
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PMID:Somatic hypermutation of the B cell receptor genes B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a). 1265 42


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