Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pleiomorphic adenoma of the salivary glands is a benign epithelial tumour occurring primarily in the major and minor salivary glands. It is by far the most common type of salivary gland tumour. Microscopically, pleiomorphic adenomas show a marked histological diversity with epithelial, myoepithelial and mesenchymal components in a variety of patterns. In addition to a cytogenetic subgroup with normal karyotypes, pleiomorphic adenomas are characterized by recurrent chromosome rearrangements, particularly reciprocal translocations, with breakpoints at 8q12, 3p21, and 12q13-15, in that order of frequency. The most common abnormality is a reciprocal t(3;8)(p21;q12). We here demonstrate that the t(3;8)(p21;q12) results in promoter swapping between PLAG1, a novel, developmentally regulated zinc finger gene at 8q12, and the constitutively expressed gene for beta-catenin (CTNNB1), a protein interface functioning in the WG/WNT signalling pathway and specification of cell fate during embryogenesis. Fusions occur in the 5'-non-coding regions of both genes, exchanging regulatory control elements while preserving the coding sequences. Due to the t(3;8)(p21;q12), PLAG1 is activated and expression levels of CTNNB1 are reduced. Activation of PLAG1 was also observed in an adenoma with a variant translocation t(8;15)(q12;q14). Our results indicate that PLAG1 activation due to promoter swapping is a crucial event in salivary gland tumourigenesis.
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PMID:Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. 902 Aug 42

Fluorescence in situ hybridization (FISH), including COBRA-FISH, was used to characterize 11 salivary gland tumors that had been investigated by banding analysis. Five cases were pleomorphic adenoma (PA), three were adenoid cystic carcinoma, and one case each was mucoepidermoid carcinoma, carcinoma ex-pleomorphic adenoma (CaPA), and adenocarcinoma. All 11 cases were selected on the basis that they had shown rearrangement of 6q or 9p or had unresolved aberrations after karyotyping. The COBRA-FISH and FISH analyses led to a revised karyotype in all informative cases and made it possible to clarify almost all chromosomal rearrangements occurring in the tumors. Of particular note were the confirmation of the existence of 6q deletions, a common change in salivary gland carcinomas, and the demonstration that a seemingly balanced t(6;9) resulted in del(6q). Other rearrangements that were revealed by FISH included amplification of 12q sequences (MDM2 and CDK4) in one PA. We also investigated the status of the PLAG1 gene in four cases (one PA, one CaPA, one adenoid cystic carcinoma, and one mucoepidermoid carcinoma) with 8q12 rearrangements. Only in the former two cases were the FISH results compatible with intragenic rearrangements. Overall, the results of the study show that, even with good banding quality and in karyotypes of modest complexity, much new information will be gained by supplementing the banding analysis with a multicolor FISH approach, such as COBRA-FISH.
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PMID:Characterization of chromosome aberrations in salivary gland tumors by FISH, including multicolor COBRA-FISH. 1113 32

Pleomorphic adenomas are the most common type of salivary gland tumours. Activation of the PLAG1 gene on chromosome 8q12 is the most frequent mutation found in these tumours. This results from chromosomal translocations leading to promoter substitution between PLAG1, mainly expressed in fetal tissue, and more broadly expressed genes. The replacement of the PLAG1 promoter, inactive in adult salivary glands, by a strong promoter derived from the translocation partner, leads to ectopic expression of PLAG1 in the tumor cells. This abnormal PLAG1 expression results in deregulation of PLAG1 target genes causing salivary gland tumorigenesis. PLAG1 binds to promoter 3 of the Insulin-like growth factor 2 gene (IGF2) and stimulates its activity. IGF2 is highly expressed in salivary gland adenomas overexpressing PLAG1 while no IGF2 expression is found in adenoma without abnormal PLAG1 expression nor in normal salivary gland tissue, indicating a perfect correlation between PLAG1 and IGF2 expression. These results provide us with the first clue for understanding the role of PLAG1 in salivary gland tumor development. IGF2 perfectly fits in the picture of a restarted developmental program with concomitant loss of differentiation, the typical hallmark for any tumour. Salivary gland genesis provides a system for studying the development of glandular organs having many basic features in common with the salivary gland, such as breast, kidney, lung, pancreas and prostate. With a unique salivary gland organ culture system we now can study principles of epitheliogenesis, tubulogenesis and branching morphogenesis. Genes expressed at the spot where during tumourigenesis proliferation overrules differentiation constitute new targets for reverting the proliferative, tumour-specific stage. By elucidating molecular mechanisms involved in human cancer, we will hence contribute at the level of fundamental cancer research (oncogenesis) and normal organ development (organogenesis).
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PMID:[Molecular techniques lead to the first insights into the pathophysiology of salivary gland adenomas]. 1128 86

Extensive cytogenetic investigations of pleomorphic adenomas of the salivary glands have unequivocally demonstrated that they are cytogenetically monoclonal and are characterized by a high frequency of tumor specific chromosome abnormalities involving in particular chromosome bands 3p21, 8q12 and 12q14-15. Here we show that two radiation-associated and cytogenetically polyclonal adenomas without gross rearrangements of these breakpoints show simultaneous overexpression of the PLAG1 and HMGIC genes, i.e. the target genes of the 8q12 and 12q14-15 rearrangements in sporadic adenomas. In addition, one of the tumors expressed a cryptic CTNNB1-PLAG1 fusion transcript. Our findings strongly suggest that identical or very similar molecular mechanisms are operating during adenoma tumorigenesis irrespective of whether the tumors are cytogenetically polyclonal or whether they have non-random, tumor specific abnormalities. Cytogenetically polyclonal adenomas are thus most likely also of monoclonal origin.
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PMID:Expression of PLAG1 and HMGIC proteins and fusion transcripts in radiation-associated pleomorphic adenomas. 1189 14

PLAG1 (pleomorphic adenoma gene 1) and PLAGL2 (PLAG-like 2) are oncogenes involved in various malignancies. Thus the study of their regulatory mechanisms may lead to identification of novel therapeutic targets. In this study, we provide supporting evidence that sumoylation and acetylation regulate functions of PLAG1 and PLAGL2. A conserved transcriptional repression domain exists in both PLAG1 and PLAGL2, whose activity depends on the presence of three sumoylation motifs and an intact sumoylation pathway. In vivo sumoylation assays confirmed that lysines 244, 263, and 353 of PLAG1 and lysines 250, 269, and 356 of PLAGL2 are indeed sumoylation sites. Further study showed that sumoylation inhibits PLAG1-induced IGF-II expression in reporter assays. The repression mediated by sumoylation may be partially explained by its effect on the cellular localization of PLAG1 and PLAGL2, because sumoylation-deficient but not wild-type PLAG1 and PLAGL2 concentrate in the nucleolus. PLAG1 and PLAGL2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by HDAC7. Interestingly, the sumoylation-deficient mutant of PLAGL2 is acetylated at a lower level than its wild-type counterpart, suggesting that some of the lysine residues may be targets for both modifications. Finally, mutation of three lysine residues in sumoylation motifs significantly impairs the transformation ability of PLAG1 and PLAGL2, suggesting the essential roles of these sites in the oncogenic potential of PLAG proteins. Taken together, the activities of PLAG1 and PLAGL2 are tightly modulated by both sumoylation and acetylation, which have opposite effects on their transactivation. To our knowledge, this is the first demonstration that oncoproteins can be regulated by both sumoylation and acetylation.
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PMID:Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. 1620 15

Pleomorphic salivary gland adenomas are characterized by recurrent chromosome rearrangements of 8q12, leading to activation of the PLAG1 oncogene. Here we demonstrate that CHCHD7-PLAG1 is a novel and recurrent gene fusion generated by a cytogenetically cryptic rearrangement in pleomorphic adenomas. CHCHD7 is a newly identified member of a multifamily of proteins containing a conserved (coiled coil 1)-(helix 1)-(coiled coil 2)-(helix 2) domain. Northern blot analysis revealed that the gene is ubiquitously expressed. Its biological function is unknown and the gene has hitherto not been associated with neoplasia. CHCHD7 and PLAG1 are located head-to-head about 500 bp apart in 8q12. Molecular analyses of 27 tumors revealed CHCHD7-PLAG1 fusions in three tumors, two of which had t(6;8) and t(8;15) translocations as the sole anomalies and one a normal karyotype. FISH analyses of interphase nuclei and nuclear chromatin fibers of a fourth adenoma with a normal karyotype revealed that a second fusion partner gene, TCEA1, located about 2 Mb centromeric to PLAG1, also is fused to PLAG1 as a result of a cryptic 8q rearrangement. The breakpoints in both fusions occur in the 5'-noncoding regions of the genes, leading to activation of PLAG1 by promoter swapping/substitution. Western blot and immunohistochemical analyses demonstrated that the PLAG1 protein was overexpressed in epithelial, myoepithelial, and mesenchymal-like tumor cells in tumors with both fusions. Our findings further emphasize the significance of PLAG1 activation in pleomorphic adenomas and demonstrate that the gene is more frequently activated than previously anticipated.
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PMID:CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas. 1673

Pleomorphic adenoma (PA), a benign mixed salivary gland tumor, has been associated with abnormal karyotypes in up to 70% of cases, with nonrandom involvement of 8q12, the locus of the pleomorphic adenoma (PLAG1) gene. In this study, cytogenetics and fluorescence in situ hybridization (FISH) were used to investigate PLAG1 involvement in PA from seven patients. There were two males and five females ranging in age from 25 to 65 years. Samples of parotid gland tissue from the tumor sites, set up as solid tumor cultures, showed a normal karyotype in two cases [46,XY;46,XX] and cytogenetic abnormalities in five cases (71%). The abnormalities comprised one variant translocation [t(1;4;8)(p32;q35;q12)], two classic translocations [t(5;8)(p13;q12)], one novel deletion [del(12)(p11.2p12.1)], and a novel insertion [ins(9;8)(p22;q12q21.1)]. FISH was performed in all cases by using two probes from the RP11 library, flanking PLAG1; a sequence 1.48 megabases (Mb) upstream and another 2.27 Mb downstream, covering a total area of 3.8 Mb. The PLAG1 gene was intact and normally situated in four cases - the 46,XY, 46,XX, del(12p), and one t(5;8). PLAG1 was disrupted in three cases - one t(5;8), ins(9;8), and t(1;4;8). In addition, genomic instability was seen in two cases, one with PLAG1 amplification in the form of a homogeneously staining region, and the other in der(8) ring formation. The data provide further unique cases showing the complexity of PLAG1 gene rearrangements in PA.
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PMID:Heterogeneity of PLAG1 gene rearrangements in pleomorphic adenoma. 1769 84

Lipoblastoma is a benign uncommon soft-tissue-tumor resembling fetal adipose tissue affecting mainly children under three years of age. In lipoblastoma, the typical cytogenetic changes are clonal rearrangements involving chromosomal region 8q11-->q13. The oncogene PLAG1 (pleomorphic adenoma gene 1) is located within this chromosomal region on band 8q12. Recent reports have demonstrated that in lipoblastoma, the PLAG1 gene is activated by 'promoter-swapping'. Herein, we demonstrate that in lipoblastoma, the PLAG1 gene may also be activated by low-level amplification. We report on a lipoblastoma with the karyotype 48 approximately 50,XX,del(8)(q13q21.2),+del(8)(q13q21.2)x4[cp12]. Subsequent FISH analysis on uncultured tumor cells confirmed this result and demonstrated a low-level amplification of the chromosomal region 8pter-->8q13 and 8q21.2-->8qter. A partial monosomy was seen for the chromosomal region 8q13-->8q21.2. No other gains or losses were observed by CGH analysis. RT-PCR analysis showed that the PLAG1 gene is activated in the tumor sample of the lipoblastoma analyzed, in contrast to normal fatty tissue without PLAG1 expression. In conclusion, our results demonstrate that low-level amplification is a further mechanism of PLAG1 activation in lipoblastomas.
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PMID:PLAG1 activation in lipoblastoma coinciding with low-level amplification of a derivative chromosome 8 with a deletion del(8)(q13q21.2). 1816 Jul 79

The incidence of salivary gland tumor in Poland is growing in the last two decades. Simultaneously a progress in understanding the genetic mechanisms of formation of this tumor was achieved by detecting several genes like PLAG1 involved in its pathogenesis. In this study we perform a whole genome, CGH analysis with the aim to identify recurrent, chromosomal copy number changes possibly indicating novel tumor suppressor gene or oncogene loci. 29 salivary tumor samples: Cystadenolymphoma-warthin (15) and adenoma polymorphum (14) located in the parotid (27) and submandibular gland (2) were collected and CGH was performed. The established copy number profiles were compared in order to asses the smallest common region of gains and losses. The delineated regions were further analyzed with the UCSC Genome Browser on Human Mar. 2006 Assembly to asses their gene content. Altogether, salivary gland tumors presented a different aberration pattern than these reported for head and neck squamous cell carcinoma (HNSCC) but no significant differences were observed between Warthin and adenoma polymorphum tumors. Moreover, several potential tumor suppressor genes and oncogenes were identified in the smallest, common altered regions. We show a frequent deletion of the harakiri gene (12q24.2) in 12/29 tumors and TP53 gene (17p13.1) in 11/29 tumors as potential tumor suppressors in salivary gland cancers. Besides, we detected a frequent amplification of the 13q22.1-22.2 region in 13/29 cases harboring the KLF5 and KLF12 genes. KLF5 regulates the expression of survivin, an oncogene widely expressed in the majority of human cancers. The observed alterations may indicate important genetic events in the formation of salivary gland tumors. Especially the amplification in 13q may be a mechanism contributing to the expression of survivin and tumor progression.
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PMID:Chromosomal gains and losses indicate oncogene and tumor suppressor gene candidates in salivary gland tumors. 1819 Feb 42

Myoepithelioma, mixed tumor and parachordoma are uncommon soft tissue tumors thought to represent morphological variants of a single tumor type. The genetic basis of these neoplasms is poorly understood. However, they morphologically resemble mixed tumor of the salivary glands (also known as pleomorphic adenoma), a tumor characterized by deregulated expression of PLAG1 or HMGA2. To evaluate a possible genetic relationship between these soft tissue and salivary gland tumors, PLAG1 expression levels and the genomic status of PLAG1 and HMGA2 were investigated in five soft tissue myoepitheliomas and one pleomorphic adenoma. In addition, all tumors were cytogenetically investigated and whole genome DNA copy number imbalances were studied in five of them. The genetic profiles were heterogeneous and the only aberration common to all soft tissue myoepitheliomas was a minimally deleted region of 3.55 Mb in chromosome band 19p13. Recurrent deletion of CDKN2A suggests that inactivation of this tumor suppressor gene is pathogenetically important in a subset. Furthermore, PLAG1 rearrangement was found in a soft tissue tumor from a patient previously treated for a salivary pleomorphic adenoma, indicating either metastasis of the salivary gland lesion or that some soft tissue tumors develop through the same mechanisms as their salivary gland counterparts.
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PMID:Heterogeneous genetic profiles in soft tissue myoepitheliomas. 1860 93


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