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1.
CNS Oncol ; 13(1): 2347824, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38869444

ABSTRACT

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.


[Box: see text].


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzimidazoles , Carbamates , Cetuximab , Colorectal Neoplasms , Mutation , Proto-Oncogene Proteins B-raf , Sulfonamides , Humans , Cetuximab/therapeutic use , Cetuximab/administration & dosage , Male , Middle Aged , Proto-Oncogene Proteins B-raf/genetics , Carbamates/therapeutic use , Sulfonamides/therapeutic use , Benzimidazoles/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/secondary , Central Nervous System Neoplasms/pathology
2.
CNS Oncol ; 13(1): 2357532, 2024 Dec 31.
Article in English | MEDLINE | ID: mdl-38873961

ABSTRACT

Aim: Glioneuronal and neuronal tumors are rare primary central nervous system malignancies with heterogeneous features. Due to the rarity of these malignancies diagnosis and treatment remains a clinical challenge. Methods: Here we performed a narrative review aimed to investigate the principal issues concerning the diagnosis, pathology, and clinical management of glioneuronal tumors. Results: Diagnostic criteria have been recently overturned thanks to a better characterization on a histological and molecular biology level. The study of genomic alterations occurring within these tumors has allowed us to identify potential therapeutic targets including BRAF, FGFR, and PDGFRA. Conclusion: Techniques allowing molecular sequencing DNA methylation assessment of the disease are essential diagnostic tools. Targeting agents should be included in the therapeutic armamentarium after loco-regional treatment failure.


[Box: see text].


Subject(s)
Brain Neoplasms , Humans , Young Adult , Brain Neoplasms/therapy , Brain Neoplasms/genetics , Brain Neoplasms/diagnosis , Brain Neoplasms/pathology , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/drug therapy , Glioma/therapy , Glioma/genetics , Glioma/diagnosis , Glioma/pathology
3.
Pathol Res Pract ; 259: 155367, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38797130

ABSTRACT

Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3 bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.


Subject(s)
Central Nervous System Neoplasms , Proto-Oncogene Proteins , Repressor Proteins , Humans , Repressor Proteins/genetics , Proto-Oncogene Proteins/genetics , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/metabolism , Child , Adolescent , Male , Female , Infant , Child, Preschool , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Tandem Repeat Sequences , Gene Duplication
4.
Cancer Cell ; 42(6): 968-984.e9, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38788719

ABSTRACT

Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.


Subject(s)
Glioblastoma , Membrane Glycoproteins , Receptors, Immunologic , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Receptors, Immunologic/metabolism , Receptors, Immunologic/genetics , Humans , Animals , Mice , Glioblastoma/genetics , Glioblastoma/pathology , Glioblastoma/metabolism , Myeloid Cells/metabolism , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Cell Line, Tumor , Mice, Inbred C57BL , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/metabolism
5.
JCO Precis Oncol ; 8: e2300470, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38691815

ABSTRACT

PURPOSE: Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor-defined SCLC subtype on incidence and outcomes of brain metastases (BMs). METHODS: Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N-, (2) A+/N+, (3) A-/N+, and (4) A-/N-. Cumulative incidence competing risk analyses were used to assess incidence of CNS progression. Cox proportional hazards models were used for multivariable analyses of overall survival (OS) and CNS progression-free survival (CNS-PFS). RESULTS: Of 164 patients, most were either A+/N- or A+/N+ (n = 62, n = 63, respectively). BMs were present at diagnosis in 24 patients (15%). Among them, the 12-month cumulative incidence of subsequent CNS progression was numerically highest for A+/N- (50% [95% CI, 10.5 to 74.7]; P = .47). Among those BM-free at diagnosis, the 12-month cumulative incidence of CNS progression was numerically the highest for A+/N- (16% [95% CI, 7.5 to 27.9]) and A-/N+ (9.1% [95% CI, 0.0 to 34.8]; P = .20). Both subtypes, A+/N- and A-/N+, had worse OS compared with A+/N+ (A+/N-: hazard ratio [HR], 1.62 [95% CI, 1.01 to 2.51]; P < .05; A-/N+: HR, 3.02 [95% CI, 1.35 to 6.76]; P = .007). Excellent response rates (28, 65% CR/PR) across subtypes were seen in patients who had CNS-directed radiotherapy versus systemic therapy alone (9, 36% CR/PR). CONCLUSION: To our knowledge, this report is the first to investigate CNS-specific outcomes based on transcription factor subtypes in patients with SCLC. BM-free patients at diagnosis with A+/N- or A-/N+ subtypes had worse outcomes compared with those with transcriptional factor coexpression. Further investigation into the mechanisms and implications of SCLC subtyping on CNS-specific outcomes is warranted to ultimately guide personalized care.


Subject(s)
Brain Neoplasms , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology , Small Cell Lung Carcinoma/secondary , Male , Female , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Middle Aged , Prognosis , Aged , Brain Neoplasms/secondary , Brain Neoplasms/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Adult , Aged, 80 and over , Central Nervous System Neoplasms/secondary , Central Nervous System Neoplasms/genetics , Retrospective Studies
6.
Nat Commun ; 15(1): 3634, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38688897

ABSTRACT

Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to the low prevalence of pediatric CNS tumors, major advances in targeted therapies have been lagging compared to other adult tumors. We collect single nuclei RNA-seq data from 84,700 nuclei of 35 pediatric CNS tumors and three non-tumoral pediatric brain tissues and characterize tumor heterogeneity and transcriptomic alterations. We distinguish cell subpopulations associated with specific tumor types including radial glial cells in ependymomas and oligodendrocyte precursor cells in astrocytomas. In tumors, we observe pathways important in neural stem cell-like populations, a cell type previously associated with therapy resistance. Lastly, we identify transcriptomic alterations among pediatric CNS tumor types compared to non-tumor tissues, while accounting for cell type effects on gene expression. Our results suggest potential tumor type and cell type-specific targets for pediatric CNS tumor treatment. Here we address current gaps in understanding single nuclei gene expression profiles of previously under-investigated tumor types and enhance current knowledge of gene expression profiles of single cells of various pediatric CNS tumors.


Subject(s)
Central Nervous System Neoplasms , Ependymoma , Gene Expression Regulation, Neoplastic , Transcriptome , Humans , Child , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/metabolism , Ependymoma/genetics , Ependymoma/pathology , Ependymoma/metabolism , Child, Preschool , Astrocytoma/genetics , Astrocytoma/pathology , Astrocytoma/metabolism , Gene Expression Profiling/methods , Female , RNA-Seq , Male , Adolescent , Neural Stem Cells/metabolism , Neural Stem Cells/pathology , Cell Nucleus/metabolism , Cell Nucleus/genetics
7.
J Clin Neurosci ; 124: 36-46, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38642434

ABSTRACT

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and there is limited research on its tumor microenvironment (TME). Nevertheless, more and more studies have evidence that TME has essential effects on tumor cell proliferation, immune escape, and drug resistance. Thus, it is critical to elucidate the role of TME in PCNSL. The understanding of the PCNSL TME is gradually unfolding, including factors that distinguish it from systemic diffuse large B-cell lymphoma (DLBCL). The TME in PCNSL exhibits both transcriptional and spatial intratumor heterogeneity. Cellular interactions between tumor cells and stroma cells reveal immune evasion signaling. The comparative analysis between PCNSL and DLBCL suggests that PCNSL is more likely to be an immunologically deficient tumor. In PCNSL, T cell exhaustion and downregulation of macrophage immune function are accompanied by suppressive microenvironmental factors such as M2 polarized macrophages, endothelin B receptor, HLA depletion, PD-L1, and TIM-3. MMP-9, Integrin-ß1, and ICAM-1/LFA-1 play crucial roles in transendothelial migration towards the CNS, while CXCL13/CXCR5, CD44, MAG, and IL-8 are essential for brain parenchymal invasion. Further, macrophages, YKL-40, CD31, CD105, PD-1/PD-L1 axis, osteopontin, galectin-3, aggregative perivascular tumor cells, and HLA deletion may contribute to poor outcomes in patients with PCNSL. This article reviews the effect of various components of TME on the progression and prognosis of PCNSL patients to identify novel therapeutic targets.


Subject(s)
Central Nervous System Neoplasms , Tumor Microenvironment , Humans , Tumor Microenvironment/immunology , Tumor Microenvironment/physiology , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/immunology , Prognosis , Lymphoma, Non-Hodgkin/pathology
8.
J Neurooncol ; 168(2): 367-373, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38639853

ABSTRACT

PURPOSE: Central nervous system (CNS) embryonal tumors are a diverse group of malignant tumors typically affecting pediatric patients that recently have been better defined, and this paper describes evolution of a unique type of embryonal tumor at relapse. METHODS: Two pediatric patients with CNS embryonal tumors with EWSR1-PLAGL1 rearrangements treated at Arkansas Children's Hospital with histopathologic and molecular data are described. RESULTS: These two patients at diagnosis were classified as CNS embryonal tumors with EWSR1-PLAGL1 rearrangements based on histologic appearance and molecular data. At relapse both patient's disease was reclassified as atypical teratoid rhabdoid tumor (ATRT) based on loss of INI-1, presence of SMARCB1 alterations, and methylation profiling results. CONCLUSION: CNS embryonal tumors with EWSR1-PLAGL1 rearrangements acquire or include a population of cells with SMARCB1 alterations that are the component that predominate at relapse, suggesting treatment aimed at this disease component at diagnosis should be considered.


Subject(s)
Central Nervous System Neoplasms , Neoplasm Recurrence, Local , Neoplasms, Germ Cell and Embryonal , RNA-Binding Protein EWS , SMARCB1 Protein , Female , Humans , Male , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Gene Rearrangement , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasms, Germ Cell and Embryonal/genetics , Neoplasms, Germ Cell and Embryonal/pathology , Rhabdoid Tumor/genetics , Rhabdoid Tumor/pathology , RNA-Binding Protein EWS/genetics , SMARCB1 Protein/genetics , Infant
9.
Genes (Basel) ; 15(4)2024 04 09.
Article in English | MEDLINE | ID: mdl-38674407

ABSTRACT

Multidrug resistance (MDR) commonly leads to cancer treatment failure because cancer cells often expel chemotherapeutic drugs using ATP-binding cassette (ABC) transporters, which reduce drug levels within the cells. This study investigated the clinical characteristics and single nucleotide variant (SNV) in ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2, and their association with mortality in pediatric patients with central nervous system tumors (CNST). Using TaqMan probes, a real-time polymerase chain reaction genotyped 15 SNPs in 111 samples. Patients were followed up until death or the last follow-up day using the Cox proportional hazards model. An association was found between the rs1045642 (ABCB1) in the recessive model (HR = 2.433, 95% CI 1.098-5.392, p = 0.029), and the ICE scheme in the codominant model (HR = 9.810, 95% CI 2.74-35.06, p ≤ 0.001), dominant model (HR = 6.807, 95% CI 2.87-16.103, p ≤ 0.001), and recessive model (HR = 6.903, 95% CI 2.915-16.544, p = 0.038) significantly increased mortality in this cohort of patients. An association was also observed between the variant rs3114020 (ABCG2) and mortality in the codominant model (HR = 5.35, 95% CI 1.83-15.39, p = 0.002) and the dominant model (HR = 4.421, 95% CI 1.747-11.185, p = 0.002). A significant association between the ICE treatment schedule and increased mortality risk in the codominant model (HR = 6.351, 95% CI 1.831-22.02, p = 0.004, HR = 9.571, 95% CI 2.856-32.07, p ≤ 0.001), dominant model (HR = 6.592, 95% CI 2.669-16.280, p ≤ 0.001), and recessive model (HR = 5.798, 95% CI 2.411-13.940, p ≤ 0.001). The genetic variants rs3114020 in the ABCG2 gene and rs1045642 in the ABCB1 gene and the ICE chemotherapy schedule were associated with an increased mortality risk in this cohort of pediatric patients with CNST.


Subject(s)
Central Nervous System Neoplasms , Multidrug Resistance-Associated Protein 2 , Polymorphism, Single Nucleotide , Humans , Male , Female , Child , Child, Preschool , Infant , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/pathology , Cohort Studies , Adolescent , Multidrug Resistance-Associated Proteins/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Genetic Markers/genetics , Neoplasm Proteins/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Biomarkers, Tumor/genetics
10.
J Neuropathol Exp Neurol ; 83(7): 579-585, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38687613

ABSTRACT

Advanced molecular testing has increasingly become an integral component for accurate diagnosis of central nervous system (CNS) tumors. We sought to establish the current state of molecular testing availability and approaches for the diagnosis of CNS tumors in US hospitals that conduct high volumes of CNS tumor resections. We distributed a 16-item survey inquiring about molecular testing approaches for CNS tumors to 115 neuropathologists at US hospitals with neurosurgery residency programs. Thirty-five neuropathologists (30.4%) responded to the survey, all of whom indicated their institutions perform molecular testing on CNS tumor tissue. The most commonly offered tests were MGMT methylation profiling and next-generation sequencing. Fourteen respondents (40%) indicated that their institution is able to test for and report all of the molecular alterations included in our survey. Nine (25.7%) respondents indicated that molecular testing is performed as standard of care for all patients with resected CNS tumors. Our results suggest that even in academic hospitals with a high volume of CNS tumor resections, molecular testing for these tumors is limited. Continued initiatives are necessary to expand the availability of molecular testing for CNS tumors to ensure diagnostic accuracy and guide targeted therapy.


Subject(s)
Central Nervous System Neoplasms , Humans , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/diagnosis , United States , Hospitals , Surveys and Questionnaires
11.
J Neurooncol ; 168(3): 537-545, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38647646

ABSTRACT

PURPOSE: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients. METHODS: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed. RESULTS: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers. CONCLUSION: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins. GERMAN CLINICAL TRIALS REGISTER REGISTRATION NUMBER: DRKS00029553, date of registration 08/16/2022, retrospectively registered.


Subject(s)
Hemangioblastoma , von Hippel-Lindau Disease , Humans , von Hippel-Lindau Disease/genetics , von Hippel-Lindau Disease/complications , Hemangioblastoma/surgery , Hemangioblastoma/genetics , Hemangioblastoma/pathology , Male , Female , Adolescent , Child , Retrospective Studies , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/surgery , Cerebellar Neoplasms/pathology , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/surgery , Central Nervous System Neoplasms/pathology , Follow-Up Studies , Von Hippel-Lindau Tumor Suppressor Protein/genetics
12.
Acta Neuropathol Commun ; 12(1): 60, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637838

ABSTRACT

Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.


Subject(s)
Brain Neoplasms , Central Nervous System Neoplasms , Glioma , Neoplasms, Neuroepithelial , Adult , Humans , Central Nervous System Neoplasms/diagnostic imaging , Central Nervous System Neoplasms/genetics , Neoplasms, Neuroepithelial/diagnostic imaging , Neoplasms, Neuroepithelial/genetics , Neoplasms, Neuroepithelial/pathology , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioma/genetics , Methylation , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Repressor Proteins/genetics , CREB-Binding Protein/genetics
13.
Acta Neuropathol Commun ; 12(1): 55, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38581034

ABSTRACT

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.


Subject(s)
Brain Neoplasms , Central Nervous System Neoplasms , Ependymoma , Glioma, Subependymal , Supratentorial Neoplasms , Child , Humans , Brain Neoplasms/genetics , Cell Cycle Proteins , Central Nervous System Neoplasms/genetics , Ependymoma/pathology , In Situ Hybridization, Fluorescence , Supratentorial Neoplasms/pathology , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics
14.
Nat Commun ; 15(1): 3635, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38688903

ABSTRACT

Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.


Subject(s)
Central Nervous System Neoplasms , DNA Methylation , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Humans , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/pathology , Child , Histone Deacetylases/metabolism , Histone Deacetylases/genetics , Epigenomics/methods , Repressor Proteins/metabolism , Repressor Proteins/genetics , Single-Cell Analysis , Transcription, Genetic , Cytosine/metabolism
15.
Am J Surg Pathol ; 48(7): 874-882, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38501656

ABSTRACT

ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.


Subject(s)
Hemangioblastoma , Kidney Neoplasms , Mutation , TOR Serine-Threonine Kinases , Tuberous Sclerosis Complex 2 Protein , Humans , Hemangioblastoma/genetics , Hemangioblastoma/pathology , Hemangioblastoma/chemistry , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/chemistry , Female , Male , Tuberous Sclerosis Complex 2 Protein/genetics , Adult , Middle Aged , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , DNA Mutational Analysis , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/chemistry , Immunohistochemistry , Tuberous Sclerosis Complex 1 Protein/genetics , Aged , Genetic Predisposition to Disease , Adolescent , Phenotype , Young Adult , Child , High-Throughput Nucleotide Sequencing
16.
Acta Neuropathol Commun ; 12(1): 42, 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38500181

ABSTRACT

Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.


Subject(s)
Brain Neoplasms , Central Nervous System Neoplasms , Neoplasms, Germ Cell and Embryonal , Humans , Brain Neoplasms/pathology , Nuclear Proteins/genetics , Transcription Factors/genetics , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Neoplasms, Germ Cell and Embryonal/genetics , Bromodomain Containing Proteins , Cell Cycle Proteins , Forkhead Transcription Factors , Homeodomain Proteins
17.
J Mol Diagn ; 26(6): 447-455, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38378079

ABSTRACT

Microarray-based methylation profiling has emerged as a valuable tool for refining diagnoses and revealing novel tumor subtypes, particularly in central nervous system tumors. Despite the increasing adoption of this technique in clinical genomic laboratories, no technical standards have been published in establishing minimum criteria for test validation. A working group with experience and expertise in DNA-based methylation profiling tests on central nervous system tumors collaborated to develop practical discussion points and focus on important considerations for validating this test in clinical laboratory settings. The experience in validating this methodology in a clinical setting is summarized. Specifically, the advantages and challenges associated with utilizing an in-house classifier compared with a third-party classifier are highlighted. Additionally, experiences in demonstrating the assay's sensitivity and specificity, establishing minimum sample criteria, and implementing quality control metrics are described. As methylation profiling for tumor classification expands to other tumor types and continues to evolve for various other applications, the critical considerations described here are expected to serve as a guidance for future efforts in establishing professional guidelines for this assay.


Subject(s)
DNA Methylation , Oligonucleotide Array Sequence Analysis , Humans , Oligonucleotide Array Sequence Analysis/methods , Oligonucleotide Array Sequence Analysis/standards , Reproducibility of Results , Sensitivity and Specificity , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/diagnosis , Gene Expression Profiling/methods
18.
Eur J Cancer ; 201: 113951, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38417299

ABSTRACT

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.


Subject(s)
Adenocarcinoma of Lung , Antineoplastic Agents , Central Nervous System Neoplasms , Lung Neoplasms , Humans , Lung Neoplasms/genetics , Lung Neoplasms/surgery , Lung Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Japan , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/drug therapy , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/surgery , Adenocarcinoma of Lung/drug therapy , ErbB Receptors/genetics , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/surgery , Central Nervous System Neoplasms/drug therapy , Mutation , Recurrence , Central Nervous System/pathology , Protein Kinase Inhibitors/therapeutic use , Retrospective Studies
19.
Diagn Pathol ; 19(1): 39, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38388383

ABSTRACT

BACKGROUND: This study aimed to investigate the clinicopathological characteristics, diagnostic indicators, and critical factors for the differential diagnosis of rosette-forming glioneuronal tumor (RGNT). PATIENTS AND METHODS: This retrospective study included six surgically treated RGNT cases. We analyzed and summarized their clinical manifestations, radiological features, histological morphology, immunophenotype, and molecular genetic changes, supplemented with a literature review. RESULTS: The patients comprised four males and two females with a mean age of 35 years. The tumors were located in the cerebellum (two cases); the fourth ventricle, quadrigeminal cistern, and third ventricle (one case each); and the fourth ventricle and brainstem (one case). Clinical manifestations included headaches in four cases, left eyelid ptosis in one case, and one asymptomatic case only identified during physical examination. Microscopically, the tumor cells were uniform in size and were marked by rosette-like or pseudorosette-like structures around the neuropil and blood vessels. Immunohistochemistry revealed biphasic patterns. The central neuropil components of the rosette-like structures around the neuropil and the pseudorosette structures of the perivascular regions expressed Syn, while the cells surrounding the rosettes expressed Olig2 and not GFAP. GFAP and S-100 were expressed in the glial components but not in the rosette or pseudorosette regions. The Ki-67 proliferation index was typically low. Molecular genetic analysis showed that the main molecular changes involved FGFR1 mutation accompanied by PIK3R1 mutation. None of the patients received chemoradiotherapy postoperatively. Follow-up durations varied between 4 and 23 months with no recorded recurrence or metastasis. CONCLUSION: RGNT is a comparatively rare mixed glioneuronal tumor that occurs in the midline structures. Its morphology shows certain overlaps with other low-grade neuroepithelial tumors. Identifying the rosettes around the neuropil is critical for morphological diagnosis, and the molecular identification of FGFR1 mutations accompanied by PIK3R1 mutations can facilitate diagnosis.


Subject(s)
Brain Neoplasms , Neoplasms, Neuroepithelial , Adult , Female , Humans , Male , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Diagnosis, Differential , Fourth Ventricle/pathology , Mutation , Neoplasms, Neuroepithelial/genetics , Neoplasms, Neuroepithelial/pathology , Retrospective Studies
20.
BMC Cancer ; 24(1): 219, 2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38365640

ABSTRACT

BACKGROUND: Breast cancer is a common cause for central nervous system (CNS) metastasis, resulting in a significant reduction in overall survival. Germline pathogenic variants (PVs) in BRCA1/2 are the most common genetic risk factor for breast cancer, associated with poor prognostic factors. This study sought to explore the patterns and outcome of CNS metastases in breast cancer patients with germline PVs in BRCA1/2 genes. METHODS: A retrospective cohort of 75 breast cancer patients with known BRCA1/2 mutation status, who were diagnosed with CNS metastases in 2006-2021. Histopathology, characteristics of CNS disease, treatments, and survival were compared between BRCA1/2 carriers (n = 25) and non-carriers (n = 50), using propensity score matching (1:2 ratio) to control for the possible influence of tumor receptor status (ER, PR, HER2) and patient age. Pearson chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. RESULTS: Patients with PVs in BRCA1/2 had more high-grade tumors (88% vs. 68%, P = 0.060), were younger at CNS disease diagnosis (median 46.69 vs. 55.02 years, P = 0.003) and had better ECOG performance status (ECOG PS 0 in 20% vs. 2%, P = 0.033), but without significant differences in systemic or CNS-directed treatment approaches. BRCA1/2 mutation was associated with a higher rate of temporal lobe involvement (52% vs. 26%, P = 0.026) and leptomeningeal spread (40% vs. 20%, P = 0.020). Survival after diagnosis of CNS disease was shorter (median 8.03 vs. 28.36 months, P < 0.0001), with no significant differences in time to development of CNS metastases or overall-survival. CONCLUSION: Patients with CNS metastatic breast cancer and PVs in BRCA1/2 showed a higher rate of leptomeningeal and temporal lobe involvement, and a shorter survival with CNS disease. To the best of our knowledge, this is the first study suggesting an exclusive impact of germline BRCA1/2 mutations in CNS metastatic breast cancer.


Subject(s)
BRCA1 Protein , BRCA2 Protein , Breast Neoplasms , Central Nervous System Neoplasms , Female , Humans , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/pathology , Central Nervous System , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/secondary , Germ Cells/pathology , Germ-Line Mutation , Matched-Pair Analysis , Prognosis , Retrospective Studies
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