Sporadic adamantinomatous craniopharyngioma with double-hit somatic APC mutations.
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ABSTRACT:
SUBMITTER: Hong CS
PROVIDER: S-EPMC8446933 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7283019 | biostudies-literature
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| S-EPMC7610141 | biostudies-literature
Project description:RNA sequencing of 18 human ACP samples, 3 foetal pituitaries, 3 non functioning pituitary adenomas
2018-04-11 | E-MTAB-5267 | biostudies-arrayexpress
Project description:Craniopharyngioma is a benign tumor, and the predominant treatment methods are surgical resection and radiotherapy. However, both treatments may lead to complex complications, seriously affecting patients' survival rate and quality of life. Adamantinomatous craniopharyngioma (ACP), as one of the histological subtypes of craniopharyngioma, is associated with a high incidence and poor prognosis, and there is a gap in the targeted therapy of immune-related genes for ACP. In this study, two gene expression profiles of ACP, namely GSE68015 and GSE94349, were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified by the Limma package, and 271 differentially expressed immune-related genes (DEIRGs) were obtained from the Immport database. The gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed for annotation, visualization, and integrated discovery. Five hub genes, including CXCL6, CXCL10, CXCL11, CXCL13, and SAA1, were screened out through protein-protein interaction (PPI) network interaction construction. Two diagnostic markers, namely S100A2 and SDC1 (both of which have the Area Under Curve value of 1), were screened by the machine learning algorithm. CIBERSORT analysis showed that M2 macrophages, activated NK cells, and gamma delta T cells had higher abundance in ACP infiltration, while CD8+ T cells, regulatory T cells, and Neutrophils had less abundance in ACP infiltration. The expression of gamma delta T cells was positively correlated with CXCL6, S100A2, SDC1, and SAA1, while CD8+ T cells expression was negatively correlated with CXCL6, S100A2, SDC1, and CXCL10. ACP with high CXCL6 showed remarkable drug sensitivity to Pentostatin and Wortmannin via CellMiner database analysis. Our results deepened the understanding of the molecular immune mechanism in ACP and provided potential biomarkers for the precisely targeted therapy for ACP.
| S-EPMC9006448 | biostudies-literature
Project description:Abstract BACKGROUND Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. Genetically engineered mouse models of ACP demonstrate that perturbation of the fetal anterior pituitary can generate tumors analogous to ACP. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control, with the most common agent being the humanized monoclonal antibody, tocilizumab. This agent demonstrated poor blood-brain barrier (BBB) penetration in primates. We present findings from two children enrolled on a phase 0 clinical trial (NCT03970226) of a single dose of preoperative intravenous tocilizumab prior to resection of newly diagnosed ACP. METHODS Blood samples were obtained at multiple timepoints. Serum was isolated via ficoll separation. Tumor tissue and cyst fluid were obtained 4–6 hours following the single IV dose of tocilizumab. Tissue was snap-frozen. Tumor was homogenized in RIPA buffer. Free tocilizumab in serum, cyst fluid, and tumor tissue was measured using enzyme-linked immunosorbent assay (ELISA) against a standard curve. RESULTS Both patients in this trial demonstrated clinically relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and tumor tissue, compared to undetectable levels in control samples. CONCLUSION ACP resides outside BBB protection. In addition to demonstrating the feasibility of systemic delivery of tocilizumab, these findings indicate that other large molecules, including those known to have poor BBB penetration, may be systemically delivered as part of an antitumor regimen in the treatment of ACP.
| S-EPMC7715731 | biostudies-literature
Project description:RNA Sequencing of Adamantinomatous Craniopharyngioma
| PRJEB18056 | ENA
Project description:Purpose:Several recent studies have documented CTNNB1 and BRAF mutations which are mutually exclusive for adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) tumors. This discovery is helpful in the development of novel targeted therapies in successful clinical trials with BRAF mutations in PCP cases. However, no such targeted therapy is available yet for ACP. Here, we report novel mutations, which are not previously reported, in a case of an adult ACP using NGS analysis. Results:Patient DNA was sequenced using Ion PI v3 chip on Ion Proton. A total of 16 variants were identified in this tumor by NGS analysis, out of which four were missense mutations, seven were synonymous mutations, and five were intronic variants. In CTNNB1 gene a known missense mutation in c.101G>T; in TP53 a known missense mutation in c.215C>G; and two known missense variants in PIK3CA, viz., in c.1173A>G; in exon 7, and in c.3128T>C; in exon 21, were found, respectively. Seven synonymous mutations were detected in this tumor, viz., in IDH1 (rs11554137), in FGFR3 (rs7688609), in PDGFRA (rs1873778), in APC (COSM3760869), in EGFR (rs1050171), in MET (rs35775721), and in RET (rs1800861), respectively. Three known, intronic variants were found in genes, such as PIK3CA, KDR, and JAK3, respectively. Also, a 3'-UTR and a splice site acceptor site variant in CSF1R and FLT3 genes were found in this tumor. We have shown allele coverage, allele ratio, and p-value, for all these mutations. The p-values and Phred quality score were significantly high for these variants. Conclusion:As reported in previous studies, in ACP tumors we found a CTNNB1 mutation by NGS analysis. The PIK3CA variants we detected were not known previously in ACP tumors. Finding the PIK3CA mutations in the ACP tumors may help develop targeted therapy for a subset of craniopharyngiomas with PIK3CA activating mutations. Clinical trials are in progress with specific PIK3CA inhibitors in advanced stages of many cancers.
| S-EPMC7183340 | biostudies-literature
Project description:PurposeCraniopharyngiomas (CPs) are benign tumors, complete tumor resection is considered to be the optimal treatment. However, although histologically benign, the local invasiveness of CPs commonly contributes to incomplete resection and a poor prognosis. At present, some advocate less aggressive surgery combined with radiotherapy as a more reasonable and effective means of protecting hypothalamus function and preventing recurrence in patients with tight tumor adhesion to the hypothalamus. Hence, if a method can be developed to predict the invasiveness of CP preoperatively, it will help in the development of a more personalized surgical strategy. The aim of the study was to report a radiomics-clinical nomogram for the individualized preoperative prediction of the invasiveness of adamantinomatous CP (ACPs) before surgery.MethodsIn total, 1,874 radiomics features were extracted from whole tumors on contrast-enhanced T1-weighted images. A support vector machine trained a predictive model that was validated using receiver operating characteristic (ROC) analysis on an independent test set. Moreover, a nomogram was constructed incorporating clinical characteristics and the radiomics signature for individual prediction.ResultsEleven features associated with the invasiveness of ACPs were selected by using the least absolute shrinkage and selection operator (LASSO) method. These features yielded area under the curve (AUC) values of 79.09 and 73.5% for the training and test sets, respectively. The nomogram incorporating peritumoral edema and the radiomics signature yielded good calibration in the training and test sets with the AUCs of 84.79 and 76.48%, respectively.ConclusionThe developed model yields good performance, indicating that the invasiveness of APCs can be predicted using noninvasive radiological data. This reliable, noninvasive tool can help clinical decision making and improve patient prognosis.
| S-EPMC7925821 | biostudies-literature
Project description:Abnormal DNA methylation plays a role in tumor progression and is becoming recognized as a prognostic marker in various types of cancers. In this study, we aimed to investigate the association between DNA methylation and clinicopathological features, prognosis, and outcomes in patients with Adamantinomatous craniopharyngioma (ACPs). To achieve this, we analyzed the global methylation profile of 35 tumors using the Illumina Infinium HumanMethylation850 BeadChip.
2024-03-14 | GSE239695 | GEO
Project description:Activating mutations in the gene encoding ?-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a histologically benign but aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours. Recently, we generated an ACP mouse model and revealed that, as in human ACP, nucleocytoplasmic accumulation of ?-catenin (?-cat(nc)) and over-activation of the Wnt/?-catenin pathway occurs only in a very small proportion of cells, which form clusters. Here, combining mouse genetics, fluorescence labelling and flow-sorting techniques, we have isolated these cells from tumorigenic mouse pituitaries and shown that the ?-cat(nc) cells are enriched for colony-forming cells when cultured in stem cell-promoting media, and have longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells (PSCs). Global gene profiling analysis has revealed that these ?-cat(nc) cells express high levels of secreted mitogenic signals, such as members of the SHH, BMP and FGF family, in addition to several chemokines and their receptors, suggesting an important autocrine/paracrine role of these cells in the pathogenesis of ACP and a reciprocal communication with their environment. Finally, we highlight the clinical relevance of these findings by showing that these pathways are also up-regulated in the ?-cat(nc) cell clusters identified in human ACP. As well as providing further support to the concept that pituitary stem cells may play an important role in the oncogenesis of human ACP, our data reveal novel disease biomarkers and potential pharmacological targets for the treatment of these devastating childhood tumours.
| S-EPMC3400760 | biostudies-literature