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Malignant Tumours of the Salivary Glands
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Vincent Vander Poorten, Patrick J. Bradley
Pleomorphic adenoma gene 1 (PLAG1) is a specific proto-oncogene found in a large percentage of pleomorphic adenomas and is transcribed and overexpressed following a t(3;8)(p21;q12) chromosome translocation resulting in β-catenin-promoter swapping. This causes deregulated expression of PLAG1 target genes by the IGF-II/IGFIR mitogenic signalling pathway. Another fusion oncogene, MEC translocated 1 gene with exons 2–5 of the mastermind-like gene (MECT1-MAML2), t(11;19)(q14–21;p12–13) is transcribed into a fusion protein that was initially thought to be exclusive for low-grade MEC. However, high-grade fusion-positive MEC cancers associated with advanced-stage lethal disease have now been described. For AdCC, a recurrent reciprocal translocation of t(6;9)(q22–23; p23–24) resulting in fusion gene partners comprising MYB gene and the transcription factor NFIB (previously reported in AdCC of breast and, lacrimal and ceruminal glands) has now been described. In both fusion-positive and a subset of fusion-negative AdCCs, high expression of the transcript Myb was found, suggesting this to be a potential target for new therapies.
Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Joaquina Baranda, Stafinur Atay, Andrew K. Godwin
More recently, Agaram and colleagues used microarray analysis to compare gene expression in 13 tumor nodule samples from eight WT pediatric GIST patients (2 within the Carney Triad) to five adult WT GIST samples. Again, the pediatric group formed a tight cluster that segregated from the adult group. In this study a total of 1,532 genes were found to be differentially expressed (> 2-fold change) between the two groups. To help rule out the possibility that the expression profiles were biased because all samples in the pediatric group were gastric, a second analysis was performed comparing the pediatric WT group to a group of adult gastric GISTs with varying genotype (3 WT, 4 PDGFRA mutants, 12 KIT mutants). This analysis yielded 1,335 differentially expressed genes (> 2-fold change), 814 of which were in common with the first analysis. The genes with significantly different expression in the pediatric group as compared to the adult tumors included FGF4 (fibroblast growth factor 4), BAALC (brain and acute leukemia, cytoplasmic), IGF1R, NELL1 (NEL-like 1), CRLF1 cytokine receptor-like factor 1), PLAG1 (pleomorphic adenoma gene 1) and FGF3 (fibroblast growth factor 3). The only common gene to show up in both studies was IGF1R. Although work from the Godwin group has not focused exclusively on pediatric GISTs, they have performed extensive studies on WT GISTs and were the first to report that IGF1R mRNA and protein is frequently overexpressed in WT adult and pediatric GISTs as compared with mutant GISTs [87, 93]. For example, IHC analysis on a primary GIST and a paraganglioma from the Carney triad patient shows strong IGF1R expression [87, 93]. A recent study using a larger sample set of pediatric WT GISTs (n = 9) confirmed that IGF1R is overexpressed in all pediatric cases compared to mutant GISTs [94]. With respect to IGF1R and its downstream signaling molecules, Tarn and colleagues showed that the small-molecule tyrosine kinase inhibitor, NVP-AEW541 (Novartis), which has activity against IGF1R can lead to cytotoxicity in mutant GIST cell lines, via AKT and MAPK signaling that is independent from KIT signaling. Similar findings were observed when IGF1R levels were impaired using targeted siRNAs. They observed additive effects by combining NVP-AEW541 and IM, suggesting a potential therapeutic benefit in targeting IGF1R in GISTs that are unresponsive to IM, including pediatric GISTs which overexpress IGF1R as well as combination therapies in all tumors [87].
Lacrimal gland pleomorphic adenoma with extensive necrosis
Published in Orbit, 2022
Micheal A. O’Rourke, Penelope A. McKelvie, Christopher M. Angel, Alan A. McNab
PLAG1-CTNNB1 fusion was first identified as the key event in the pathogenesis of pleomorphic adenoma by Kas et al. in 1997.17 This finding has been confirmed by multiple groups as the most common molecular event in pleomorphic adenoma and carcinoma ex pleomorphic adenoma. However, detection of PLAG1 translocation requires techniques such as FISH and RT-PCR which may not be available routinely in pathology laboratories. Fusion involving PLAG1 gene causes an overexpression and PLAG1 protein, which can be demonstrated by immunohistochemistry (IHC).18 A recent study by Katabi et al. demonstrated high sensitivity of 96% of PLAG1 IHC for pleomorphic adenoma, but a lower specificity in a cohort of other salivary gland tumours, since it has been detected in myoepithelioma, myoepithelial/epithelial carcinoma, and basal cell adenocarcinomas. In our case, the finding of myxoid stroma and positive PLAG1 immunohistochemistry confirmed the diagnosis of pleomorphic adenoma. Examining specific molecular abnormalities in lacrimal gland neoplasia shows some promise for future treatments but has not identified unique identifying markers for specific tumour types.
Myoepithelioma of bone: ultrastructural, immunohistochemical and molecular study of three cases
Published in Ultrastructural Pathology, 2019
Paweł Kurzawa, Martin K. Selig, Patryk Kraiński, Michał Dopierała, G. Petur Nielsen
Molecular studies of myoepithelial tumors have shown that pleomorphic adenomas of salivary gland harbor-deregulated expression of PLAG1 or HMGA2.14–17 Myoepithelial tumors with ductal differentiation arising in other locations also show PLAG1 rearrangement, in contrast to myoepithelial tumors of deep-seated soft tissues without ductal differentiation.17,18 EWSR1 rearrangement may be seen in up to 45% soft tissue myoepitheliomas, mixed tumors of the skin and intraosseous myoepithelial tumors,2,19–24 including EWSR1-POU5F1, EWSR1-PBX1, EWSR1-PBX3, EWSR1-ZNF444, EWSR1-ATF1, EWSR1-KLF17, and SRF-E2F1 fusions.2,19–27
The structure of CLEC-2: mechanisms of dimerization and higher-order clustering
Published in Platelets, 2021
Eleyna M Martin, Malou Zuidscherwoude, Luis a Morán, Ying Di, Angel García, Steve P Watson
An important consideration for therapeutic design targeting the CLEC-2-podoplanin interaction is the varied response between species. The affinity of CLEC-2 to human podoplanin was observed to be 24 µM and 4 µM for monomeric and dimeric CLEC-2 respectively [4,15], whereas mouse CLEC-2 was shown to bind mouse podoplanin with an affinity of 10–15 nM, for monomeric and dimeric podoplanin[26]. This suggests that structurally, at least in solution, the binding interface is tighter for the mouse counterparts. Whether this is due to structural variations in CLEC-2 or podoplanin, or differences in levels of glycosylation of recombinant podoplanin would need to be determined. Importantly however, sequence analysis reveals that the four arginine residues within the C-type lectin domain, essential to the CLEC-2-podoplanin interaction, are conserved between mouse and human. Further to this, it has been shown that maintaining the CLEC-2-podoplanin interaction requires species specific O-glycosylation within the podoplanin PLAG domains[55]. The binding motif of the PLAG1 and PLAG3 domains (EDXXXT) are conserved between mouse and human, with the crucial species difference that the O-glycan essential to the interaction is present in PLAG1 of mouse podoplanin but PLAG3 of human podoplanin[65]. Additionally, Sekiguchi et al [54]. having identified the PLAG4 domain within podoplanin as a contributor to CLEC-2 binding, suggest simultaneous inhibition of the human PLAG3/4 would be required for complete suppression of podoplanin-mediated tumor growth and metastasis. Considerations such as the post-translational modifications and multimerisation ability of CLEC-2 and its ligands, which may affect binding activity, warrant the need for standardized preparations in CLEC-2 research.