CNTF, COMT, DDR1, DISC1, DRD2, DRD3 es DTNBP1 kandidáns gének vizsgálata szkizofréniában: eredmények a Magyar SCHIZOBANK Konzorcium vizsgálataból

Schizophrenia is a chronic, debilitating psychiatric disorder characterized by heterogeneous clinical symptoms. Although the pathogenesis of this disorder is poorly understood, several lines of evidence support the role of both common and rare genetic variants in the etiology of schizophrenia. Common variants, single nucleotide polymorphisms can be investigated by candidate gene association studies or genome-wide association studies, while rare variants, single nucleotide variants are assessable by means of candidate gene resequencing or whole-exome and genome sequencing using next generation sequencing. In this study we investigated polymorphisms of 7 candidate genes in a Hungarian schizophrenia cohort. Candidate genes were chosen on the basis of previous results and biological plausibility. 390 patients were recruited in 5 centers in the framework of the Hungarian SCHIZOBANK Consortium, the schizophrenia sample was contrasted to 1069 healthy control individuals. In this sample SNPs of DDR1 and DRD2 genes demonstrated significant association with schizophrenia. The role of DDR1 and DRD2 genes in the etiology of schizophrenia warrant further investigation, based on their genomic localization and biological functions

Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

The transcriptional landscape of Shh medulloblastoma

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.info:eu-repo/semantics/publishedVersio

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Imaging of pediatric brain tumors using somatostatin analogue 111Ih-DTPA-D-Phe1-octreotide. Gyermekkori agytumorok vizsgálata szomatosztatin-analóg (111In-DTPA-D-Phe1-octreotide) alkalmazásával

Gyermekkorban a leggyakoribb gyermekkori szolid tumor az agytumor. Az agytumorokat (beleértve a medulloblastomát is) kombinált műtéti-, sugár- és kemoterápiával kezeljük. A kemoterápiának azonban korlátozott hatása van. A gyermekkori agytumorok (különösen a medulloblastoma) szomatosztatinreceptorokat expresszálnak. A jelen vizsgálat célja, hogy megvizsgálja a gyermekkori agytumorokban a szomatosztatinreceptor-státust. A Semmelweis Egyetem II. sz. Gyermekgyógyászati Klinikájának onkológiai részlegén 2000 és 2005 között 45, agydaganattal kezelt gyermeknél végeztünk 56 Octreoscan (111In-DTPA-D-Phe1-octreotide) SPECT vizsgálatot. A 45 gyermekbôl 21 esetben (46,7%) volt a szövettani diagnózis medulloblastoma. Az Octreoscan-vizsgálattal párhuzamosan MRI-felvételeket is készítettünk. Az 56 Octreoscan-vizsgálat közül 27-nél (48,2%) találtunk egyértelműen kóros aktivitásfelvételt. Ezek közül 16 medulloblastoma, 4 ependymoma, 4 astrocytoma, illetve 3 glioblastoma volt. Az 56 (100%) Octreoscan-vizsgálatból 37 esetben (66,1%) a szcintigram és az elvégzett MRI-vizsgálatok eredményei megegyeztek, 19 vizsgálati eredménynél (33,9%) azonban a két vizsgáló eljárás eltérő eredményt mutatott. Gyermekkori agytumoros betegeknél (beleértve a MBL-t is) az Octreoscanvizsgálat differenciáldiagnózis felállítására nem megfelelő, de a tumorsejtek szomatosztatinreceptoraihoz kötődő (111In-DTPA-D-Phe1-octreotide) izotóp vegyület kimutatása alkalmas lehet a terápiás hatás nyomon követésére. Az Octreoscan-felvételt mutató tumorokban szóba jön a szomatosztatin adjuváns terápiás használata. Malignant solid tumors and leukemias are the second most common causes of death in childhood. The most frequent pediatric solid tumors are brain tumors. Brain tumors, especially medulloblastoma should be treated by surgery, irradiation and chemotherapy. However, chemotherapy has only moderate effect. Pediatric brain tumors, especially medulloblastomas, express somatostatin receptors. The aim of this study was the investigation of the expression of somatostatin receptors in pediatric brain tumors for diagnostic and therapeutic purpose. Fifty-six scintigraphic imagings (111In-DTPA-D-Phe1-octreotide) made in 45 children treated with brain tumor at the Unit of Oncology of the 2nd Department of Pediatrics, Semmelweis University. The diagnosis was medulloblastoma in 21 cases (46.7%). MRI scans have been performed parallel with the Octreoscan images. Octreoscan images were positive in 27 of 56 (48.2%) cases. The 27 positive Octreoscan images consisted of 16 medulloblastomas, 4 ependymomas, 4 astrocytomas and 3 glioblastomas. In 37 (66.1%) cases the results of Octreoscans were the same as those of the MRI scans. However, in 19 scans (33.9%) the outcome was different. Octreoscan imaging is not suitable for differential diagnosis in pediatric brain tumors, including medulloblastomas. Isotopes specifically binding to the somatostatin receptors (111In-DTPA-D-Phe1-octreotide) can be applied in medulloblastomas for diagnosis and follow-up treatment. In Octreoscan-positive tumors the Octreoscan images establish the opportunity to somatostatin analogue and/or specifically targeted radiation therapies