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PURPOSE: Angioleiomyoma, predominantly arising from the extremities, is a benign soft tissue tumor. Reports on its intracranial location are rare. We assessed clinical, radiological, and pathological features of intracranial angioleiomyoma (iALM) treated at our neurosurgical institution. METHODS: We consecutively enrolled all patients with neuropathologically confirmed iALM treated at a single neurosurgical institution between 2013 and 2021. Clinical and imaging data were collected, and histological tissue sections were analyzed. A review of the literature on iALM was conducted. RESULTS: Seven patients with iALM (four female) with a median age of 45 years (range: 32-76 years) were identified. In three cases, the lesion was found incidentally. In magnetic resonance imaging (MRI), all tumors were hypo- to isointense on T1-weighted, hyperintense on T2-weighted sequences, and gadolinium-enhancing. A strong FLAIR signal was seen in six patients. Surgery consisted of gross total resection in all cases without perioperative complications. Neuropathological staining was positive for smooth muscle actin (SMA) in all lesions. Mature smooth muscle cells arranged around blood vessels were typically observed. The Ki-67 index was ≤ 3%. The patients were discharged after a median of 6 days (range: 4-9 days). During a median follow-up time of 14 months (range: 4-41 months), no tumor recurrence occurred. In the current literature, 42 additional cases of iALM were identified. CONCLUSION: Intracranial angioleiomyoma is a benign soft tissue tumor treated by gross total resection. Tumor morphology and positive staining for SMA lead to the neuropathological diagnosis.
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Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
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Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Metilación de ADN , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Aprendizaje Automático no Supervisado , Adulto JovenRESUMEN
AIMS: Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by hypomorphic mutations of NBS1. NBS1 is a member of the MRE11-RAD50-NBS1 (MRN) complex that binds to DNA double-strand breaks and activates the DNA damage response (DDR). Nbs1 inactivation in neural progenitor cells leads to microcephaly and premature death. Interestingly, p53 homozygous deletion rescues the NBS1-deficient phenotype allowing long-term survival. The objective of this work was to determine whether simultaneous inactivation of Nbs1 and p53 in neural progenitors triggered brain tumorigenesis and if so in which category this tumour could be classified. METHODS: We generated a mouse model with simultaneous genetic inactivation of Nbs1 and p53 in embryonic neural stem cells and analysed the arising tumours with in-depth molecular analyses including immunohistochemistry, array comparative genomic hybridisation (aCGH), whole exome-sequencing and RNA-sequencing. RESULTS: NBS1/P53-deficient mice develop high-grade gliomas (HGG) arising in the olfactory bulbs and in the cortex along the rostral migratory stream. In-depth molecular analyses using immunohistochemistry, aCGH, whole exome-sequencing and RNA-sequencing revealed striking similarities to paediatric human HGG with shared features with radiation-induced gliomas (RIGs). CONCLUSIONS: Our findings show that concomitant inactivation of Nbs1 and p53 in mice promotes HGG with RIG features. This model could be useful for preclinical studies to improve the prognosis of these deadly tumours, but it also highlights the singularity of NBS1 among the other DNA damage response proteins in the aetiology of brain tumours.
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Glioma , Proteína p53 Supresora de Tumor , Animales , Niño , Humanos , Ratones , Proteínas de Ciclo Celular/genética , Glioma/genética , Homocigoto , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias Neuroepiteliales , Humanos , Adulto Joven , Biomarcadores de Tumor/genética , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Fusión Génica , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Proteínas Tirosina Quinasas Receptoras/genética , Proteína Nuclear Ligada al Cromosoma X/genéticaRESUMEN
OBJECTIVE: Inhibition of the MAPK pathway by MEK inhibitors (MEKi) is currently a therapeutic standard in several cancer types, including ovarian low-grade serous carcinoma (LGSC). A common MAPK pathway alteration in tubo-ovarian high-grade serous carcinoma (HGSC) is the genomic inactivation of neurofibromin 1 (NF1). The primary objectives of our study were to survey the prevalence of NF1 inactivation in the principal ovarian carcinoma histotype as well as to evaluate its associations with clinico-pathological parameters and key biomarkers including BRCA1/2 status in HGSC. METHODS: A recently commercialized NF1 antibody (clone NFC) was orthogonally validated on an automated immunohistochemistry (IHC) platform and IHC was performed on tissue microarrays containing 2140 ovarian carcinoma cases. Expression was interpreted as loss/inactivated (complete or subclonal) versus normal/retained. RESULTS: Loss of NF1 expression was detected in 250/1429 (17.4%) HGSC including 11% with subclonal loss. Survival of NF1-inactivated HGSC patients was intermediate between favorable BRCA1/2 mutated HGSC and unfavorable CCNE1 high-level amplified HGSC. NF1 inactivation was mutually exclusive with CCNE1 high-level amplifications, co-occurred with RB1 loss and occurred at similar frequencies in BRCA1/2 mutated versus wild-type HGSC. NF1 loss was found in 21/286 (7.3%) endometrioid carcinomas with a favorable prognostic association (p = 0.048), and in 4/64 (5.9%) LGSC, mutually exclusive with other driver events. CONCLUSIONS: NF1 inactivation occurs in a significant subset of BRCA1/2 wild-type HGSC and a subset of LGSC. While the functional effects of NF1 inactivation need to be further characterized, this signifies a potential therapeutic opportunity to explore targeting NF1 inactivation in these tumors.
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Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1 , Neurofibromina 1/genética , Inmunohistoquímica , Proteína BRCA2 , Neoplasias Ováricas/patología , Carcinoma Endometrioide/patología , Cistadenocarcinoma Seroso/patología , Carcinoma Epitelial de OvarioRESUMEN
PURPOSE: The WHO classification of Tumors of the Central Nervous System represents the international standard classification for brain tumors. In 2021 the 5th edition (WHO CNS5) was published, and this review summarizes the changes regarding IDH-mutant gliomas and discusses unsolved issues and future perspectives. METHODS: This review is based on the 5th edition of the WHO Blue Book of CNS tumors (WHO CNS5) and relevant related papers. RESULTS: Major changes include taxonomy and nomenclature of IDH-mutant gliomas. Essential and desirable criteria for classification were established considering technical developments. For the first time molecular features are not only relevant for the classification of IDH-mutant gliomas but may impact grading as well. CONCLUSION: WHO CNS5 classification moves forward towards a classification which is founded on tumor biology and serves clinical needs. The rapidly increasing knowledge on the molecular landscape of IDH-mutant gliomas is expected to further refine classification and grading in the future.
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Neoplasias Encefálicas , Glioma , Humanos , Mutación , Glioma/diagnóstico , Glioma/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Sistema Nervioso Central/patología , Organización Mundial de la Salud , Isocitrato Deshidrogenasa/genéticaRESUMEN
Accessory nerve schwannoma is a rare entity in patients presenting with cranial nerve (CN) deficits. Most of these tumours arise from the cisternal segment of the eleventh CN and extend caudally. Herein, we report the third case of an accessory schwannoma extending cranially into the fourth ventricle. A 61-year-old female presented with a history of variable headaches. Cerebral magnetic resonance imaging (cMRI) revealed a large inhomogeneous contrast-enhancing lesion at the craniocervical junction extending through the foramen of Magendi and concomitant hydrocephalus due to obstruction of the foramina of Luschkae. Microsurgical tumour resection was performed in the half-sitting position. Intraoperatively, the tumour arose from a vestigial fascicle of the spinal accessory nerve. At three month follow-up, neither radiological tumour recurrence nor neurological deficits were observed.
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AIMS: Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities. METHODS: Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next-generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis. RESULTS: The majority of tumours designated as anaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric-type high-grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low-grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident. CONCLUSIONS: In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Ganglioglioma , Glioma , Niño , Humanos , Ganglioglioma/patología , Estudios Retrospectivos , Glioma/patología , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias del Sistema Nervioso Central/patología , Isocitrato DeshidrogenasaRESUMEN
Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
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Neoplasias Encefálicas/patología , Isocitrato Deshidrogenasa/genética , Oligodendroglioma/patología , Sarcoma/patología , Adulto , Anciano , Neoplasias Encefálicas/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Oligodendroglioma/genética , Sarcoma/genéticaRESUMEN
PURPOSE: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy. METHODS: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected. RESULTS: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI. CONCLUSION: A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.
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Neoplasias Encefálicas , Terapia Molecular Dirigida , Humanos , Mutación , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Proteínas Proto-Oncogénicas B-raf , Estudios RetrospectivosRESUMEN
Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.
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Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/genética , Proteómica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Barrera Hematoencefálica/patología , Línea Celular Tumoral , Niño , Estudios de Cohortes , Biología Computacional , Femenino , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Humanos , Masculino , Persona de Mediana Edad , Familia de Multigenes/genética , Proteínas de Neoplasias/líquido cefalorraquídeo , Estudios Prospectivos , Espectrometría de Masa por Ionización de Electrospray , Adulto JovenRESUMEN
AIMS: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours. METHODS: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis. RESULTS: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test). CONCLUSION: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.
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Neoplasias del Oído/patología , Saco Endolinfático/patología , Proteínas Supresoras de Tumor/metabolismo , Enfermedad de von Hippel-Lindau/patología , Adulto , Neoplasias del Oído/complicaciones , Neoplasias del Oído/genética , Saco Endolinfático/metabolismo , Humanos , Persona de Mediana Edad , Mutación/genética , Riesgo , Proteínas Supresoras de Tumor/genética , Enfermedad de von Hippel-Lindau/complicaciones , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
AIMS: KIAA1549-BRAF fusions occur in certain brain tumours and provide druggable targets due to a constitutive activation of the MAP-kinase pathway. We introduce workflows for calling the KIAA1549-BRAF fusion from DNA methylation array-derived copy number as well as DNA panel sequencing data. METHODS: Copy number profiles were analysed by automated screening and visual verification of a tandem duplication on chromosome 7q34, indicative of the KIAA1549-BRAF fusion. Pilocytic astrocytomas of the ICGC cohort with known fusion status were used for validation. KIAA1549-BRAF fusions were called from DNA panel sequencing data using the fusion callers Manta, Arriba with modified filtering criteria and deFuse. We screened DNA methylation and panel sequencing data of 7790 specimens from brain tumour and sarcoma entities. RESULTS: We identified the fusion in 337 brain tumours with both DNA methylation and panel sequencing data. Among these, we detected the fusion from copy number data in 84% and from DNA panel sequencing data in more than 90% using Arriba with modified filters. While in 74% the KIAA1549-BRAF fusion was detected from both methylation array-derived copy number and panel sequencing data, in 9% it was detected from copy number data only and in 16% from panel data only. The fusion was almost exclusively found in pilocytic astrocytomas, diffuse leptomeningeal glioneuronal tumours and high-grade astrocytomas with piloid features. CONCLUSIONS: The KIAA1549-BRAF fusion can be reliably detected from either DNA methylation array or DNA panel data. The use of both methods is recommended for the most sensitive detection of this diagnostically and therapeutically important marker.
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Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/genética , Perfilación de la Expresión Génica/métodos , Proteínas de Fusión Oncogénica/análisis , Análisis de Secuencia de ADN/métodos , Biomarcadores de Tumor/genética , Metilación de ADN , Dosificación de Gen , HumanosRESUMEN
Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Meningioma/genética , Meningioma/patología , Niño , Estudios de Cohortes , Metilación de ADN/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Progresión de la Enfermedad , Epigénesis Genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Inmunohistoquímica , Masculino , Mutación/genética , Recurrencia Local de Neoplasia , Resultado del Tratamiento , Adulto JovenRESUMEN
Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in children, adolescents and young adults (median age 14 years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and/or germline mutations in DNA mismatch repair genes (MLH1, MSH6, MSH2) were found in all cases, except one case with a family and personal history of colon cancer and another case with MSH6-deficiency available only as recurrent tumor. Loss of at least one of the mismatch repair proteins was detected via immunohistochemistry in all, but one case analyzed. Tumors displayed a hypermutant genotype and microsatellite instability was present in more than half of the sequenced cases. Integrated somatic mutational and chromosomal copy number analyses showed frequent inactivation of TP53, RB1 and activation of RTK/PI3K/AKT pathways. In contrast to the majority of IDH-mutant gliomas, more than 60% of the samples in our cohort presented with an unmethylated MGMT promoter. While the rate of immuno-histochemical ATRX loss was reduced, variants of unknown significance were more frequently detected possibly indicating a higher frequency of ATRX inactivation by protein malfunction. Compared to reference cohorts of other IDH-mutant gliomas, primary mismatch repair-deficient IDH-mutant astrocytomas have by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features. The findings reveal a so far unknown entity of IDH-mutant astrocytoma with high prognostic relevance. Diagnosis can be established by aligning with the characteristic DNA methylation profile, by DNA-sequencing-based proof of mismatch repair deficiency or immunohistochemically demonstrating loss-of-mismatch repair proteins.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Reparación de la Incompatibilidad de ADN/genética , Isocitrato Deshidrogenasa/genética , Adolescente , Adulto , Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Niño , Metilación de ADN , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Inestabilidad de Microsatélites , Mutación/genética , Recurrencia Local de Neoplasia , Pronóstico , Transducción de Señal/genética , Análisis de Supervivencia , Proteína Nuclear Ligada al Cromosoma X/genética , Adulto JovenRESUMEN
Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación de ADN , Glioblastoma/genética , Glioblastoma/patología , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/patología , Fosfohidrolasa PTEN/genética , Proteínas de Unión a Retinoblastoma/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 7/genética , Estudios de Cohortes , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Variaciones en el Número de Copia de ADN , Femenino , Eliminación de Gen , Proteína Ácida Fibrilar de la Glía/biosíntesis , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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Proteínas de Ciclo Celular/genética , Ependimoma/genética , Neoplasias Supratentoriales/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Niño , Femenino , Humanos , Masculino , Fusión de OncogenesRESUMEN
PURPOSE: Lynch Syndrome (LS) is a cancer-predisposing condition resulting from hereditary mutation of DNA mismatch repair genes. Gastrointestinal, urogenital, and endometrial carcinomas are well-known to predominantly occur in LS patients. In contrast, there are only few reports on brain tumours in the context of LS and to date intracranial tumour manifestation appear to be rather coincidental. METHODS: We present the case of a 56-year-old female developing aggressive lactotroph pituitary adenoma following a history of multiple Lynch-associated malignomas and having a confirmed MSH2 mutation. Furthermore, we performed a literature review via PubMed using the search terms 'Lynch Syndrome', 'HNPCC', 'MMR mutation' combined with 'intracranial tumour', 'sellar tumour', 'pituitary adenoma', or 'pituitary carcinoma', focusing on other reported cases and treatment regimens. RESULTS: A handful of studies have indicated an increased frequency of brain tumours in the context of LS, predominantly glioblastoma and less frequently low-grade glioma or other brain tumours. Based on our literature review, we summarized the known instances of pituitary adenoma in LS patients, including the present case. Furthermore, we reviewed the common recommendation of using temozolomide (TMZ) for treatment of aggressive pituitary adenoma or carcinoma and found strong indication that it might be insufficient in LS patients, while PD-1 blockade could be a promising treatment option. CONCLUSIONS: Combined with our case, there is a growing body of evidence that intracranial tumours and in particular those of the sellar region might be more prevalent in LS patients than previously assumed, due to their genetic profile substantially affecting viability and efficacy of treatment options. Clinical signs of aggressive tumour growth in combination with irresponsiveness to standard treatment in case of recurrence should lead to further diagnostic measures, because revelation of germline MMR mutations would call for an extended screening for other neoplastic manifestations and would markedly influence further treatment.
RESUMEN
Diffuse IDH-mutant astrocytic tumors are rarely diagnosed in the cerebellum or brainstem. In this multi-institutional study, we characterized a series of primary infratentorial IDH-mutant astrocytic tumors with respect to clinical and molecular parameters. We report that about 80% of IDH mutations in these tumors are of non-IDH1-R132H variants which are rare in supratentorial astrocytomas. Most frequently, IDH1-R132C/G and IDH2-R172S/G mutations were present. Moreover, the frequencies of ATRX-loss and MGMT promoter methylation, which are typically associated with IDH mutations in supratentorial astrocytic tumors, were significantly lower in the infratentorial compartment. Gene panel sequencing revealed two samples with IDH1-R132C/H3F3A-K27M co-mutations. Genome-wide DNA methylation as well as chromosomal copy number profiling provided further evidence for a molecular distinctiveness of infratentorial IDH-mutant astrocytomas. Clinical outcome of patients with infratentorial IDH-mutant astrocytomas is significantly better than that of patients with diffuse midline gliomas, H3K27M-mutant (p < 0.005) and significantly worse than that of patients with supratentorial IDH-mutant astrocytomas (p = 0.028). The presented data highlight the very existence and distinctiveness of infratentorial IDH-mutant astrocytomas that have important implications for diagnostics and prognostication. They imply that molecular testing is critical for detection of these tumors, since many of these tumors cannot be identified by immunohistochemistry applied for the mutated IDH1-R132H protein or loss of ATRX.
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Astrocitoma/genética , Astrocitoma/patología , Neoplasias Infratentoriales/genética , Neoplasias Infratentoriales/patología , Isocitrato Deshidrogenasa/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas-including the prognostically relevant SDH mutations-are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.