RESUMO
Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR's, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence.
Assuntos
Metilação de DNA , Glândula Pineal , Pinealoma , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Pinealoma/genética , Pinealoma/patologia , Adolescente , Adulto Jovem , Criança , Glândula Pineal/patologia , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pré-Escolar , Variações do Número de Cópias de DNARESUMO
Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animais , Camundongos , Glioblastoma/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Haploinsuficiência , Glioma/genética , PTEN Fosfo-Hidrolase/genética , Diester Fosfórico Hidrolases/genética , Linhagem Celular Tumoral , Neoplasias Encefálicas/genéticaRESUMO
Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.K28M (K27M) mutation and without involvement of the midline structures, so-called "diffuse hemispheric glioma with H3 p.K28M (K27M) mutation" (DHG-H3 K27), have been reported. Herein, we describe 2 additional cases of radiologically confirmed DHG-H3 K27 and summarize previously reported cases. We performed histological, immunohistochemical, molecular, and DNA methylation analysis and provided clinical follow-up in both cases. Overall, DHG-H3 K27 is an unusual group of diffuse gliomas that shows similar clinical, histopathological, genomic, and epigenetic features to DMG-H3 K27 as well as enrichment for activating alterations in MAPK pathway genes. These findings suggest that DHG-H3 K27 is closely related to DMG-H3 K27 and may represent an unusual presentation of DMG-H3 K27 without apparent midline involvement and with frequent MAPK pathway activation. Detailed reports of additional cases with clinical follow-up will be important to expand our understanding of this unusual group of diffuse gliomas and to better define the clinical outcome and how to classify DHG-H3 K27.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Criança , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Histonas/genética , Glioma/genética , Glioma/patologia , Mutação/genética , EpigenômicaRESUMO
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.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Embrionárias de Células Germinativas , Humanos , Neoplasias Encefálicas/patologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular , Fatores de Transcrição Forkhead , Proteínas de HomeodomínioRESUMO
Immature neuroectodermal tissue can be found in the ovary as part of an immature teratoma or as part of a teratoma with malignant neuroectodermal transformation. Such lesions may closely resemble central nervous system tumors, but their biologic similarity is unclear. We describe an 18-yr-old female who presented with abdominal pain caused by an ovarian mass with widespread metastases. Histology showed a primitive, high-grade tumor arising in the background of a mature teratoma. The tumor was SOX10 positive, with focal expression of GFAP, S100, NSE, and synaptophysin. Molecular analysis demonstrated co-amplification of PDGFRA and KIT , alterations common in high-grade gliomas. By whole-genome methylation profiling, it clustered into the "diffuse pediatric-type high-grade glioma, RTK1 subtype, subclass c" group. Despite progressing through 2 lines of chemotherapy with widespread metastatic disease, she achieved an excellent response to chemotherapy directed toward aggressive germ cell tumors. This case emphasizes the importance of immunohistochemical, genomic, and epigenetic analyses to accurately classify these exceedingly rare tumors and determine the optimal therapy.
Assuntos
Glioma , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Teratoma , Humanos , Feminino , Criança , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Teratoma/complicações , Teratoma/genética , Glioma/complicações , Glioma/genéticaRESUMO
PURPOSE OF REVIEW: The purpose of this review is to describe the commonly used molecular diagnostics and illustrate the prognostic importance to the more accurate diagnosis that also may uncover therapeutic targets. RECENT FINDINGS: The most recent WHO Classification of Central Nervous System Tumours (2021) lists over 100 distinct tumor types. While traditional histology continues to be an important component, molecular testing is increasingly being incorporated as requisite diagnostic criteria. Specific molecular findings such as co-deletion of the short arm of chromosome 1 (1p) and long arm of chromosome 19 (19q) now define IDH-mutant gliomas as oligodendroglioma. In recent years, DNA methylation profiling has emerged as a dynamic tool with high diagnostic accuracy. The integration of specific genetic (mutations, fusions) and epigenetic (CpG methylation) alterations has led to diagnostic refinement and the discovery of rare brain tumor types with distinct clinical outcomes. Molecular profiling is anticipated to play an increasing role in routine surgical neuropathology, although costs, access, and logistical concerns remain challenging. SUMMARY: This review summarizes the current state of molecular testing in neuro-oncology highlighting commonly used and developing technologies, while also providing examples of new tumor types/subtypes that have emerged as a result of improved diagnostic precision.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Oligodendroglioma , Humanos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Mutação/genéticaRESUMO
Recent studies exploring the impact of methylation in tumor evolution suggest that although the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Because changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression history of a tumor via single-cell lineage tree reconstruction. In this work, we introduce the first principled distance-based computational method, Sgootr, for inferring a tumor's single-cell methylation lineage tree and for jointly identifying lineage-informative CpG sites that harbor changes in methylation status that are retained along the lineage. We apply Sgootr on single-cell bisulfite-treated whole-genome sequencing data of multiregionally sampled tumor cells from nine metastatic colorectal cancer patients, as well as multiregionally sampled single-cell reduced-representation bisulfite sequencing data from a glioblastoma patient. We show that the tumor lineages constructed reveal a simple model underlying tumor progression and metastatic seeding. A comparison of Sgootr against alternative approaches shows that Sgootr can construct lineage trees with fewer migration events and with more in concordance with the sequential-progression model of tumor evolution, with a running time a fraction of that used in prior studies. Lineage-informative CpG sites identified by Sgootr are in inter-CpG island (CGI) regions, as opposed to intra-CGIs, which have been the main regions of interest in genomic methylation-related analyses.
Assuntos
Metilação de DNA , Neoplasias , Humanos , Metilação de DNA/genética , Sulfitos , Análise de Sequência de DNA/métodos , Genoma , Neoplasias/genética , Ilhas de CpG/genéticaRESUMO
Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.
Assuntos
Neoplasias Encefálicas , Ependimoma , Fluorocarbonos , Glioma , Humanos , Histonas/genética , Histonas/metabolismo , Lisina/genética , Ependimoma/patologia , Glioma/genética , Glioma/patologia , Rombencéfalo/patologia , Mutação/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologiaRESUMO
The uncommon MN1-altered primary central nervous system (CNS) tumors were recently added to the World Health Organization 2021 classification under the name Astroblastoma, MN1-altered. Another term used to describe them, "High-grade neuroepithelial tumor with MN1 alteration" (HGNET-MN1), makes reference to their distinct epigenetic profile but is currently not a recommended name. Thought to occur most commonly in children and predominantly in females, MN1-altered CNS tumors are associated with typical but not pathognomonic histological patterns and are characterized by a distinct DNA methylation profile and recurrent fusions implicating the MN1 (meningioma 1) gene. Diagnosis based on histological features alone is challenging: most cases with morphological features of astroblastoma (but not all) show these molecular features, whereas not all tumors with MN1 fusions show astroblastoma morphology. There is large variability in reported outcomes and detailed clinical and therapeutic information is frequently missing. Some patients experience multiple recurrences despite multimodality treatment, whereas others experience no recurrence after surgical resection alone, suggesting large clinical and biological heterogeneity despite unifying epigenetic features and recurrent fusions. In this report, we present the demographics, tumor characteristics, treatment, and outcome (including patient-reported outcomes) of three adults with MN1-altered primary CNS tumors diagnosed via genome-wide DNA methylation and RNA sequencing. All three patients were females and two of them were diagnosed as young adults. By reporting our neuropathological and clinical findings and comparing them with previously published cases we provide insight into the clinical heterogeneity of this tumor. Additionally, we propose a model for prospective, comprehensive, and systematic collection of clinical data in addition to neuropathological data, including standardized patient-reported outcomes.
RESUMO
PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFß signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Camundongos , Humanos , Glioblastoma/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Temozolomida/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacologiaAssuntos
Neoplasias Encefálicas , Epilepsia Resistente a Medicamentos , Glioma , Feminino , Humanos , Pessoa de Meia-Idade , Glioma/patologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Imageamento por Ressonância MagnéticaRESUMO
High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Neurofibromatose 1 , Humanos , Neurofibromatose 1/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Homozigoto , Deleção de Sequência , Astrocitoma/genética , Astrocitoma/patologia , Mutação/genética , Metilação de DNA/genéticaRESUMO
Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioma , Neurofibromatose 1 , Adulto , Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Glioma/patologia , Homozigoto , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Deleção de SequênciaRESUMO
PURPOSE: To highlight the clinical, neuroradiographic, neuropathologic, and molecular features of histologically identified neurocytoma in a pediatric cohort and highlight the evolving use methylation profiling in providing diagnostic clarity in difficult to diagnosis pediatric brain tumors. METHODS: Five consecutive children (ages 9-13, 2 girls 3 boys) were histologically diagnosed with neurocytoma at Rady Children's Hospital San Diego from 2012 to 2018. Clinical and molecular features were analyzed with regards to treatment course and outcome. RESULTS: Presenting symptoms included seizures (n = 2), syncope (n = 1), headache (n = 2), visual disturbances (n = 2) and emesis (n = 2). Tumor location included intraventricular (n = 2), intraventricular with parenchymal spread (n = 1), and extraventricular (n = 2). Magnetic resonance imaging demonstrated reduced diffusivity (2/5), signal abnormality on susceptibility-weighted sequences (3/5), and varying degrees of contrast enhancement (4/5). All patients underwent surgical resection alone. Recurrence occurred in four children that were treated with surgery (4/4), adjuvant radiation (2/4), and chemoradiation (1/4). Neuropathologic features included positivity for GFAP (4/5), synaptophysin (4/5), NSE (2/2), NeuN (4/4), and variable Ki-67 (< 1% to 15%). Next generation sequencing (3/5) and microarray (3/5) collectively were abnormal in four of five tumors. Methylation profiling was successfully performed on four of five samples which led to modification of diagnosis in two patients and the others were either unclassifiable or confirmatory with the histologic diagnosis. Mean time to follow up was 77 months (range 44-112 months). Mean progression free survival and overall survival were 24 months (range 6 to 52 months) and 100% respectively. CONCLUSION: Neurocytomas are a rare clinical entity that warrants further investigation into molecular and pathologic prognosticating features. Methylation profiling may aid in differentiation of neurocytoma from other difficult to diagnose tumors who share similar histologic features.