Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a lymphocytic lymphoma showing a combination of two characteristic neoplasia-associated chromosomal changes: trisomy 12, commonly observed in chronic lymphocytic leukemia and lymphocytic lymphoma, and t(18;22)(q21;q11), a variant form of the t(14;18)(q32;q21) found in most follicular lymphomas. Southern blot analysis was performed using probes for the 5' end of the BCL2 gene (18q21) and for the J lambda as well as C lambda immunoglobulin genes (22q11). With these two probes, a unique rearranged fragment was detected. Thus the t(18;22)(q21;q11) can be considered as a variant translocation of t(14;18)(q32;q21). The karyotypic analysis supports the assumption that in our case trisomy 12 occurred first, and t(18;22) appeared during tumor progression as part of the clonal evolution. This is at variance with the typical t(14;18), which has never been found to occur as a secondary change.
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PMID:t(18;22)(q21;q11) with rearrangement of BCL2 as a possible secondary change in a lymphocytic lymphoma. 186 35

About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two patients with follicular lymphoma who developed tumor progression, were studied by Southern blot analysis for rearrangements of the Ig genes and the oncogenes BCL2 and MYC. In both patients, the general pattern of Ig gene rearrangements, especially of the Ig light-chain genes, and the structure of the t(14;18) breakpoint as assessed by the polymerase chain reaction (PRC) and fine restriction mapping, remained unaltered with time. However, both within the functional Ig heavy-chain allele and around the t(14;18) breakpoint, extensive secondary alterations took place. This indicates clonal evolution rather than the appearance of an independent lymphoma. In the first case with progression from follicular lymphoma to Burkitt's lymphoma 3 years after diagnosis, alterations were especially present 3' of the t(14;18) breakpoint. In the second patient with a change from follicular to diffuse centroblastic lymphoma 4 years after diagnosis, subsequent class switches from IgM to IgG and to defective IgH expression were accompanied by deletion of C mu sequences and a rearrangement of the MYC gene, respectively. Additionally, in both patients alterations in individual restriction sites occurred, which most likely were due to somatic mutations within both the functional IgH and translocated allele. Our data indicate that complex alterations of both the functional and non-functional IgH allele may accompany tumor progression and may erroneously suggest the appearance of independent clones by Southern blot analysis. It remains to be established whether these alterations are causative events or the consequence of genetic instability and clonal evolution.
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PMID:Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes. 756 20

Chromosomal translocations leading to deregulation of specific oncogenes characterize approximately 50% of cases of diffuse large B-cell lymphomas (DLBL). To characterize additional genetic features that may be of value in delineating the clinical characteristics of DLBL, we studied a panel of 96 cases at diagnosis consecutively ascertained at the Memorial Sloan-Kettering Cancer Center (MSKCC) for incidence of gene amplification, a genetic abnormality previously shown to be associated with tumor progression and clinical outcome. A subset of 20 cases was subjected to comparative genomic hybridization (CGH) analysis, which identified nine sites of chromosomal amplification (1q21-23, 2p12-16, 8q24, 9q34, 12q12-14, 13q32, 16p12, 18q21-22, and 22q12). Candidate amplified genes mapped to these sites were selected for further analysis based on their known roles in lymphoid cell and lymphoma development, and/or history of amplification in tumors. Probes for six genes, which fulfilled these criteria, REL (2p12-16), MYC (8q24), BCL2 (18q21), GLI, CDK4, and MDM2 (12q13-14), were used in a quantitative Southern blotting analysis of the 96 DLBL DNAs. Each of these genes was amplified (four or more copies) with incidence ranging from 11% to 23%. This analysis is consistent with our previous finding that REL amplification is associated with extranodal presentation. In addition, BCL2 rearrangement and/or REL, MYC, BCL2, GLI, CDK4, and MDM2 amplification was associated with advanced stage disease. These data show, for the first time, that amplification of chromosomal regions and genes is a frequent phenomenon in DLBL and demonstrates their potential significance in lymphomagenesis.
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PMID:Chromosomal and gene amplification in diffuse large B-cell lymphoma. 963 22

Rearrangement of chromosomal bands 1q21-23 is one of the most frequent chromosomal aberrations observed in hematological malignancy. The genes affected by these rearrangements remain poorly characterized. Typically, 1q21-23 rearrangements arise during tumor evolution and accompany disease-specific chromosomal rearrangements such as t(14;18) (BCL2) and t(8;14) (MYC), where they are thus thought to play an important role in tumor progression. The pathogenetic basis of this 1q21-23-associated disease progression is currently unknown. In this setting, we surveyed our series of follicular lymphoma for evidence of recurring 1q21-23 breaks and identified three cases in which a t(14;18)(q32;q21) was accompanied by a novel balanced t(1;22)(q22;q11). Molecular cloning of the t(1;22) in a cell line (B593) derived from one of these cases and detailed fluorescent in situ hybridization mapping in the two remaining cases identified the FCGR2B gene, which encodes the immunoreceptor tyrosine-based inhibition motif-bearing IgG Fc receptor, FcgammaRIIB, as the target gene of the t(1;22)(q22;q11). We demonstrate deregulation of FCGR2B leading to hyperexpression of FcgammaRIIb2 as the principal consequence of the t(1;22). This is evidence that IgG Fc receptors can be targets for deregulation through chromosomal translocation in lymphoma. It suggests that dysregulation of FCGR2B may play a role in tumor progression in follicular lymphoma.
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PMID:The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. 1061 14

The majority of follicular lymphoma and Burkitt's lymphoma are associated with reciprocal translocations involving BCL2 and cMYC, respectively. Unusual reports of aggressive lymphoma presenting with both translocations have been described as well as rare cases with a third structural alteration usually involving BCL6. The patient described here presented with aggressive high-grade lymphocytic leukemia, FAB subtype L2 (ALL-L2), and three reciprocal translocations, t(14;18)(q32;q21), t(8;14)(q24.1;q32), and t(1;2) (q22-23;p13). Despite immature morphology the leukemic blasts had a mature B-cell phenotype; they were positive for surface immunoglobulin heavy chains and negative for CD34, TdT, and CD10. Most reported dual t(14;18)/t(8;14) cases have not shown sIg and were positive for CD10. Molecular genetic analyses showed the typical rearrangements of BCL2 and cMYC as well as the FCGR2B gene on chromosome 1q23. The occurrence of a third oncogene rearrangement in association with the dual BCL2, cMYC translocations in ALL patients is very rare. To our knowledge, this is the first case where the third hit involves the FCGR2B locus. This report reiterates the poor prognosis associated with activation of cMYC together with elevated Bcl-2 expression. These data also support recent evidence that dysregulation of FCGR2B may play a role in tumor progression.
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PMID:Case of acute lymphoblastic leukemia presenting with t(14;18)/BCL2, t(8;14)/cMYC, and t(1;2)/FCGR2B. 1450 97

Caspases and inhibitor of apoptosis proteins (IAPs) are antagonizing key apoptosis regulators. Limited studies of a few IAPs indicated their roles in astrocytomas. However, the overall expression status and significance of apoptosis regulators in astrocytomas is not clear. We examined the expression profile of the caspases (CASP3, 6, 7, 8, 9, 10, and 14), APAF1, SMAC, BCL2, the IAPs (BIRC5/survivin, CIAP1, CIAP2, XIAP, and LIVIN), and the proliferation markers Ki67 and PHH3 in 78 diffusely infiltrating astrocytomas and 24 normal brain samples by immunohistochemistry. Western blotting for major caspases and IAPs and reverse transcription-polymerase chain reaction analyses for IAPs were performed on a subset of 27 fresh samples. Our data showed BIRC5 nuclear labeling index (BIRC5-N) was the apoptosis marker most significantly different in World Health Organization grade II to IV astrocytomas and most strongly associated with proliferative activity. Expression level of other apoptosis-related proteins was modest or low in astrocytomas and did not correlate significantly with tumor grade or proliferation. Apoptosis regulators and proliferation markers were not detected in astrocytes of normal brain by immunostaining. This expression profile suggested involvement of apoptosis regulators in astrocytoma tumorigenesis, but tumor progression was more closely associated with proliferative advantages of which BIRC5 nuclear expression appeared to be a manifestation.
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PMID:Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. 1695 84

Promoter CpG island hypermethylation is an important carcinogenic event in prostate adenocarcinoma. Regardless of tissue type, human cancers have in common both focal CpG island hypermethylation and global genomic hypomethylation. The present study evaluated CpG island loci hypermethylation and LINE-1 and Alu repeat hypomethylation in prostate adenocarcinoma, analysed the relationship between them, and correlated these findings with clinicopathological features. We examined 179 cases of prostate adenocarcinoma and 30 cases of benign prostate hypertrophy for the methylation status of 22 CpG island loci and the methylation levels of LINE-1 and Alu repeats using methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. The following 16 CpG island loci were found to display cancer-related hypermethylation: RASSF1A, GSTP1, RARB, TNFRSF10C, APC, BCL2, MDR1, ASC, TIG1, RBP1, COX2, THBS1, TNFRSF10D, CD44, p16, and RUNX3. Except for the last four CpG island loci, hypermethylation of each of the remaining 12 CpG island loci displayed a close association with one or more of the prognostic parameters (ie preoperative serum prostate specific antigen level, Gleason score sum, and clinical stage). Prostate adenocarcinoma with hypermethylation of each of ASC, COX2, RARB, TNFRSF10C, MDR1, TIG1, RBP1, NEUROG1, RASSF1A, and GSTP1 showed a significantly lower methylation level of Alu or LINE-1 than prostate adenocarcinoma without hypermethylation. In addition, hypomethylation of Alu or LINE-1 was closely associated with one or more of the above prognostic parameters. These data suggest that in tumour progression a close relationship exists between CpG island hypermethylation and the hypomethylation of repetitive elements, and that CpG island hypermethylation and DNA hypomethylation contribute to cancer progression.
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PMID:Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features. 1713 17

Most human lymphomas originate from transformed germinal center (GC) B lymphocytes. While activating mutations and translocations of MYC, BCL2 and BCL6 promote specific GC lymphoma subtypes, other genetic and epigenetic modifications that contribute to malignant progression in the GC remain poorly defined. Recently, aberrant expression of the TCL1 proto-oncogene was identified in major GC lymphoma subtypes. TCL1 transgenic mice offer unique models of both aggressive GC and marginal zone B-cell lymphomas, further supporting a role for TCL1 in B-cell transformation. Here, restriction landmark genomic scanning was employed to discover tumor-associated epigenetic alterations in malignant GC and marginal zone B-cells in TCL1 transgenic mice. Multiple genes were identified that underwent DNA hypermethylation and decreased expression in TCL1 transgenic tumors. Further, we identified a secreted isoform of EPHA7, a member of the Eph family of receptor tyrosine kinases that are able to influence tumor invasiveness, metastasis and neovascularization. EPHA7 was hypermethylated and repressed in both mouse and human GC B-cell non-Hodgkin lymphomas, with the potential to influence tumor progression and spread. These data provide the first set of hypermethylated genes with the potential to complement TCL1-mediated GC B-cell transformation and spread.
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PMID:Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas. 1726 20

BCL2 (bcl-2) gene family members are important regulators of apoptosis. Increasing evidence supports their modulated expression in breast cancer cells and in many cases their relation to chemotherapy response, outcome, and overall prognosis, as well as their value as important potent therapeutic targets. Investigation and increased understanding of their transcriptional regulation and their specific roles in cancer progression and therapy response will be useful for focusing research on the development of novel therapies targeted against this gene family members' expression status. In the present review, we describe current knowledge of the molecular profile of the classical and novel members of the BCL2 family of genes as a response of breast cancer cells to cytotoxic/cytostatic drugs.
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PMID:Molecular profile of the BCL2 family of the apoptosis related genes in breast cancer cells after treatment with cytotoxic/cytostatic drugs. 1866 56

The putative tumor suppressor miR145 is transcriptionally regulated by TP53 and is downregulated in many tumors; however, its role in prostate cancer is unknown. On the other hand, BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is overexpressed in various tumors, including prostate cancer, and may transcriptionally repress the apoptosis-inducing factor (AIF) gene. Although BNIP3 transcription is controlled by hypoxia-inducible factor 1alpha (also elevated in prostate cancer), we postulated the posttranscriptional regulation of BNIP3 by miR145 through bioinformatics analysis, and herein we experimentally showed that miR145 negatively regulated BNIP3 by targeting its 3'-untranslated region. Artificial overexpression of miR145 by using adenoviral vectors in prostate cancer PC-3 and DU145 cells significantly downregulated BNIP3, together with the upregulation of AIF, reduced cell growth, and increased cell death. Artificial overexpression of wild-type TP53 in PC-3 cells (which lack TP53 protein) and DU145 cells (in which mutated nonfunctioning TP53 is expressed) significantly upregulated miR145 expression with consequent effects on BNIP3 and cell behavior as with miR145 overexpression. Analysis of prostate cancer (n = 134) and benign prostate (n = 83) tissue sample showed significantly decreased miR145 and increased BNIP3 expression in prostate cancer (P < 0.001), particularly in those with tumor progression, and both molecular changes were associated with unfavorable outcome. Abnormalities of the miR145-BNIP3 pair as part of TP53-miR145-BNIP3-AIF network may play a major role in prostate cancer pathogenesis and progression.
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PMID:MicroRNA145 targets BNIP3 and suppresses prostate cancer progression. 2033 43


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