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The Pathophysiology of Male Infertility
Published in Botros Rizk, Ashok Agarwal, Edmund S. Sabanegh, Male Infertility in Reproductive Medicine, 2019
Sperm epigenetic programming are critical modulators in spermatogenesis, key gene expressions, and even in postfertilization events [80–82]. Research suggests significant impairment of male fertility status via epigenetic aberrations or hypermethylation in numerous genes, namely NTF3, SFN, PAX8, MTHFR, RASGRF1, GTL2, HRAS, KCNQ1, JHM2DA, MEST, PLAG1, D1RAS3, LIT1, SNRPN, IGF2, and H19 [81]
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.