Second-hit APC mutation in a familial adamantinomatous craniopharyngioma.
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ABSTRACT:
SUBMITTER: Gorelyshev A
PROVIDER: S-EPMC7283019 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8446933 | biostudies-literature
Project description:OBJECTIVE:Familial Mediterranean fever (FMF) has traditionally been considered an autosomal-recessive disease; however, it has been observed that a substantial number of patients with clinical FMF possess only 1 demonstrable MEFV mutation. The purpose of this study was to perform an extensive search for a second MEFV mutation in 46 patients diagnosed clinically as having FMF and carrying only 1 high-penetrance FMF mutation. METHODS:MEFV and other candidate genes were sequenced by standard capillary electrophoresis. In 10 patients, the entire 15-kb MEFV genomic region was resequenced using hybridization-based chip technology. MEFV gene expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Pyrin protein levels were examined by Western blotting. RESULTS:A second MEFV mutation was not identified in any of the patients who were screened. Haplotype analysis did not identify a common haplotype that might be associated with the transmission of a second FMF allele. Western blots did not demonstrate a significant difference in pyrin levels between patients with a single mutation and those with a double mutation; however, FMF patients of both types showed higher protein expression as compared with controls and with non-FMF patients with active inflammation. Screening of genes encoding pyrin-interacting proteins identified rare mutations in a small number of patients, suggesting the possibility of digenic inheritance. CONCLUSION:Our data underscore the existence of a significant subset of FMF patients who are carriers of only 1 MEFV mutation and demonstrate that complete MEFV sequencing is not likely to yield a second mutation. Screening for the set of the most common mutations and detection of a single mutation appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine.
| S-EPMC2753538 | biostudies-literature
Project description: Not available
| S-EPMC7610141 | biostudies-literature
Project description: Not available
| S-EPMC11320438 | 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