| 1. |
- Afshari, Maryam K., et al.
(författare)
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Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB
- 2020
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:11, s. 652-660
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Tidskriftsartikel (refereegranskat)abstract
- The pleomorphic adenoma (PA), which is the most common salivary gland neoplasm, is a benign tumor characterized by recurrent chromosome rearrangements involving 8q12 and 12q14-15. We have previously shown that thePLAG1andHMGA2oncogenes are the targets of these rearrangements. Here, we have identified previously unrecognized subsets of PAs with ins(9;8)/t(8;9) (n = 5) and ins(9;12)/t(9;12) (n = 8) and breakpoints located in the vicinity of thePLAG1andHMGA2loci. RNA-sequencing and reverse transcriptase (RT)-PCR analyses of a case with an ins(9;8) revealed a novelNFIB-PLAG1fusion in whichNFIBexon 4 is linked toPLAG1exon 3. In contrast to the developmentally regulatedPLAG1gene,NFIBwas highly expressed in normal salivary gland, indicating thatPLAG1in this case, as in other variant fusions, is activated by promoter swapping. RT-PCR analysis of three PAs with t(9;12) revealed two tumors with chimeric transcripts consisting ofHMGA2exon 4 linked toNFIBexons 9 or 3 and one case with a fusion linkingHMGA2exon 3 toNFIBexon 9. TheNFIBfusion events resulted in potent activation ofPLAG1andHMGA2. Analysis of the chromatin landscape surroundingNFIBrevealed several super-enhancers in the 5 '- and 3 '-parts of theNFIBlocus and its flanking sequences. These findings indicate thatPLAG1andHMGA2, similar toMYBin adenoid cystic carcinoma, may be activated by enhancer-hijacking events, in which super-enhancers inNFIBare translocated upstream ofPLAG1or downstream ofHMGA2. Our results further emphasize the role ofNFIBas a fusion partner to multiple oncogenes in histopathologically different types of salivary gland tumors.
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| 2. |
- Ageron, M., et al.
(författare)
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ANTARES : The first undersea neutrino telescope
- 2011
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier. - 0168-9002 .- 1872-9576. ; 656:1, s. 11-38
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Tidskriftsartikel (refereegranskat)abstract
- The ANTARES Neutrino Telescope was completed in May 2008 and is the first operational Neutrino Telescope in the Mediterranean Sea. The main purpose of the detector is to perform neutrino astronomy and the apparatus also offers facilities for marine and Earth sciences. This paper describes the design, the construction and the installation of the telescope in the deep sea, offshore from Toulon in France. An illustration of the detector performance is given. (C) 2011 Elsevier B.V. All rights reserved.
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| 3. |
- Boecker, W., et al.
(författare)
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Cellular organization and histogenesis of adenosquamous carcinoma of the pancreas: evidence supporting the squamous metaplasia concept.
- 2020
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Ingår i: Histochemistry and Cell Biology. - : Springer Science and Business Media LLC. - 0948-6143 .- 1432-119X. ; 154:1, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Adenosquamous carcinoma of the pancreas (ASCAP) is characterized by conventional pancreatic ductal adenocarcinoma (PDAC) and squamous carcinoma components with at least 30% of the tumour showing squamous differentiation. To get further insight into the histogenesis of these lesions, we analysed the cellular organization of ASCAP compared to PDACs. Using Immunohistochemistry and triple immunofluorescence labelling studies for keratins, p63, p40, MUC1, MUC2, MUC5AC, Ki67, and EGFR we demonstrate that many ASCAPs contain a transitional zone between the K8/18-positive adenocarcinomatous component and the p63+/p40+/K5/K14+squamous component initiated by the expression of p63 in K8/18+adenocarcinomatous cells and the appearance of basally located p63+K5/14+cells. p63+K5/14+cells give rise to fully developed squamous differentiation. Notably, 25% of conventional PDACs without histologically recognizable squamous component contain foci of p63+p40+and K5/14+cells similar to the transitional zone. Our data provide evidence that the squamous carcinoma components of ASCAPs originate from pre-existing PDAC via transdifferentiation of keratin K8/18-positive glandular cells to p63-, p40-, and keratin K5/14-positive squamous carcinoma cells supporting the squamous metaplasia hypothesis. Thus our findings provide new evidence about the cellular process behind squamous differentiation in ASCAPs.
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| 4. |
- Brill, L. B., 2nd, et al.
(författare)
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Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms
- 2011
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 24:9, s. 1169-76
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have shown that the recurrent t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma results in a novel fusion of the MYB proto-oncogene with the transcription factor gene NFIB. To determine the frequency of this finding, we used RT-PCR assays of the MYB and MYB-NFIB fusion transcripts, and immunohistochemistry for the MYB protein, to study adenoid cystic carcinomas and other epithelial tumors of the salivary glands, and head and neck region. MYB-NFIB fusion transcript was detected in 25 of 29 (86%) frozen adenoid cystic carcinoma tumor samples, and in 14 of 32 (44%) formalin-fixed paraffin-embedded adenoid cystic carcinoma tumor specimens. In contrast, the MYB-NFIB fusion was not expressed in non-adenoid cystic carcinoma neoplasms of the head and neck, confirming the high specificity of the MYB-NFIB fusion. Adenoid cystic carcinomas from various anatomic sites, including salivary gland, sinonasal cavity, tracheobronchial tree, larynx, breast, and vulva were repeatedly fusion-positive, indicating that adenoid cystic carcinomas located in different anatomic sites not only have important morphologic features in common, but also probably evolve through activation of the same molecular pathways. Studies of the expression of MYB revealed that 89% of the tumors, including both fusion-positive and fusion-negative cases, overexpressed MYB RNA. Similarly, 82% of adenoid cystic carcinomas stained positive for MYB protein, compared with 14% of non-adenoid cystic carcinoma neoplasms, indicating that MYB immunostaining may be useful for the diagnosis of adenoid cystic carcinoma, but that neoplasms sometimes in the differential diagnosis are also labeled. The latter are, however, fusion-negative. In summary, our studies show that MYB activation through gene fusion or other mechanisms is a major oncogenic event in adenoid cystic carcinoma occurring at various anatomic sites. In addition to being a diagnostically useful biomarker for adenoid cystic carcinoma, MYB and its downstream effectors are also novel potential therapeutic targets.
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| 5. |
- Clausen, S., et al.
(författare)
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Outcome of Ordinary Polymorphous Adenocarcinomas of the Salivary Glands in Comparison With Papillary and Cribriform Subtypes
- 2022
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 42:3, s. 1455-1463
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Polymorphous adenocarcinoma (PAC) is a low-grade salivary gland malignancy in contrast to variants with papillary (PAP) or cribriform (CASG) architecture and confers the second most common malignancy of minor salivary glands. Our study aimed to identify prognostic factors and to evaluate histomorphological and molecular diagnostic criteria of PACs. Patients and Methods: A series of 155 PACs, including 10 PAPs and 12 CASGs from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW) and the Hamburg Salivary Gland Reference Centre (HRC) were analyzed. Results: One fifth of the tumors were located in the major salivary glands and PACS/CASGS invariably lacked p40 expression. Fifty-two percent of PACs showed a PRKD1 E710D mutation. Ordinary PACs had a disease-specific 10-year survival probability of 97% compared to 90% when combining PAPs and CASGs. T-stage at diagnosis was a prognostic factor with 98% for stages T1/T2 versus 75% for T3/T4. Conclusion: Diagnostic algorithms for the PAC/CASG spectrum of tumors need to be improved and should include molecular markers.
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| 6. |
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| 7. |
- Fehr, Andre, et al.
(författare)
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A closer look at Warthin tumors and the t(11;19).
- 2008
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Ingår i: Cancer genetics and cytogenetics. - : Elsevier BV. - 0165-4608. ; 180:2, s. 135-9
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Tidskriftsartikel (refereegranskat)abstract
- The translocation t(11;19)(q21;p13) has been described in mucoepidermoid carcinoma (MEC) and rarely in Warthin tumors (WT), both tumors of the salivary gland. The translocation creates a fusion gene in which exon 1 of CRTC1 is linked to exons 2-5 of MAML2. To verify the translocation in WT, we performed nested reverse transcriptase-polymerase chain reaction using RNA from 48 WTs. This revealed the t(11;19)(q21;p13) translocation and expression of the chimeric gene in two metaplastic WT samples, but in none of the remaining ordinary 46 WTs. On review, the two positive cases were classified as tumors highly suspect for MEC. Indeed, our experience and published observations of the t(11;19)(q21;p13) translocation in WT reveal that only a small subset of WTs are positive, and that these tumors are often classified as infarcted or metaplastic WT, known to overlap considerably with MEC on purely morphological grounds. We therefore conclude that the presence of the t(11;19)(q21;p13) rearrangement favors a diagnosis of MEC.
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| 8. |
- Fehr, Andre, et al.
(författare)
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A link between the expression of the stem cell marker HMGA2, grading, and the fusion CRTC1-MAML2 in mucoepidermoid carcinoma.
- 2009
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 48:9, s. 777-85
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the concept of cancer stem cells and their expression of embryonic stem cell markers has gained considerable experimental support. In this study, we examined the expression of one such marker, the high-mobility group AT-hook 2 gene (HMGA2) mRNA, in 53 formalin-fixed, paraffin-embedded mucoepidermoid carcinomas (MEC) and four normal parotid tissues using quantitative real-time RT-PCR (qPCR). MECs are often characterized by the fusion gene CRTC1-MAML2, the detection of which is an important tool for the diagnosis and prognosis of MEC. For detection of the CRTC1-MAML2 fusion transcript, we performed RT-PCR. The mean expression level of HMGA2 was higher in fusion negative (302.8 +/- 124.4; n = 14) than in positive tumors (67.3 +/- 13.1; n = 39). Furthermore, the fusion-negative tumors were often high-grade tumors and the HMGA2 expression level rose with the tumor grade (low: 43.7 +/- 11.0, intermediate: 126.2 +/- 28.3, and high: 271.2 +/- 126.5). A significant difference was found in the HMGA2 expression levels between the different grading groups (one-way ANOVA, P = 0.04) and among the fusion-negative and -positive tumors (t-test, P = 0.05), indicating that the expression level of HMGA2 was closely linked to grading, the presence/absence of the CRTC1-MAML2 fusion, and the tumor behavior of MECs. These findings offer further evidence for the theory that the MEC group comprises two subgroups: one group with the CRTC1-MAML2 fusion, which is a group with a moderate aggressiveness and prognosis, and the other group lacking that fusion corresponding to an increased stemness, and thus, higher aggressiveness and worse prognosis.
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| 9. |
- Fehr, Andre, et al.
(författare)
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A new type of MAML2 fusion in mucoepidermoid carcinoma.
- 2008
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 47:3, s. 203-6
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Tidskriftsartikel (refereegranskat)abstract
- The present study reports for the first time a CRTC3-MAML2 fusion gene in a mucoepidermoid carcinoma, as determined by RT-PCR and sequencing. We screened a total of 67 formalin-fixed, paraffin-embedded mucoepidermoid carcinomas for the presence of chimeric genes. In one of these samples, a CRTC3-MAML2 fusion gene was detected. Thus, this report demonstrates the existence of a fusion of MAML2 with CREB regulated transcriptional coactivator CRTC3 additional to the already known fusion of MAML2 and CRTC1. Both gene fusions seem to result in an identical tumor phenotype and the fusion genes CRTC1-MAML2 and CRTC3-MAML2 may play a similar role in the development of mucoepidermoid carcinomas.
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| 10. |
- Fehr, Andre, et al.
(författare)
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Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia
- 2023
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Ingår i: Genes Chromosomes & Cancer. - : John Wiley & Sons. - 1045-2257 .- 1098-2264. ; 62:10, s. 597-606
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Tidskriftsartikel (refereegranskat)abstract
- Therapy-resistant disease is a major cause of death in patients with acute lympho-blastic leukemia (ALL). Activation of the MYB oncogene is associated with ALL and leads to uncontrolled neoplastic cell proliferation and blocked differentiation. Here, we used RNA-seq to study the clinical significance of MYB expression and MYB alter-native promoter (TSS2) usage in 133 pediatric ALLs. RNA-seq revealed that all cases analyzed overexpressed MYB and demonstrated MYB TSS2 activity. qPCR analyses confirmed the expression of the alternative MYB promoter also in seven ALL cell lines. Notably, high MYB TSS2 activity was significantly associated with relapse (p = 0.007). Moreover, cases with high MYB TSS2 usage showed evidence of therapy-resistant disease with increased expression of ABC multidrug resistance transporter genes (e.g., ABCA2, ABCB5, and ABCC10) and enzymes catalyzing drug degradation (e.g., CYP1A2, CYP2C9, and CYP3A5). Elevated MYB TSS2 activity was further associated with augmented KRAS signaling (p < 0.05) and decreased methyla-tion of the conventional MYB promoter (p < 0.01). Taken together, our results sug-gest that MYB alternative promoter usage is a novel potential prognostic biomarker for relapse and therapy resistance in pediatric ALL.
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