7 results on '"Suwala, Abigail K."'
Search Results
2. Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.
- Author
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Neyazi S, Yamazawa E, Hack K, Tanaka S, Nagae G, Kresbach C, Umeda T, Eckhardt A, Tatsuno K, Pohl L, Hana T, Bockmayr M, Kim P, Dorostkar MM, Takami T, Obrecht D, Takai K, Suwala AK, Komori T, Godbole S, Wefers AK, Otani R, Neumann JE, Higuchi F, Schweizer L, Nakanishi Y, Monoranu CM, Takami H, Engertsberger L, Yamada K, Ruf V, Nomura M, Mohme T, Mukasa A, Herms J, Takayanagi S, Mynarek M, Matsuura R, Lamszus K, Ishii K, Kluwe L, Imai H, von Deimling A, Koike T, Benesch M, Kushihara Y, Snuderl M, Nambu S, Frank S, Omura T, Hagel C, Kugasawa K, Mautner VF, Ichimura K, Rutkowski S, Aburatani H, Saito N, and Schüller U
- Subjects
- Adult, Child, Humans, Transcriptome, Gene Expression Profiling, Mutation, Epigenesis, Genetic, Ependymoma, Spinal Cord Neoplasms
- Abstract
Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
3. Genetical and epigenetical profiling identifies two subgroups of pineal parenchymal tumors of intermediate differentiation (PPTID) with distinct molecular, histological and clinical characteristics.
- Author
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Rahmanzade R, Pfaff E, Banan R, Sievers P, Suwala AK, Hinz F, Bogumil H, Cherkezov A, Kaan AF, Schrimpf D, Friedel D, Göbel K, Keller F, Saenz-Sardà X, Lossos A, Sill M, Witt O, Sakowitz OW, Korshunov A, Reuss DE, Etminan N, Unterberg A, Ratliff M, Herold-Mende C, Wick W, Pfister SM, von Deimling A, Jones DTW, and Sahm F
- Subjects
- Humans, Pinealoma genetics, Pinealoma pathology, Pineal Gland pathology, Brain Neoplasms genetics, Brain Neoplasms pathology
- Published
- 2023
- Full Text
- View/download PDF
4. Oligosarcomas, IDH-mutant are distinct and aggressive.
- Author
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Suwala AK, Felix M, Friedel D, Stichel D, Schrimpf D, Hinz F, Hewer E, Schweizer L, Dohmen H, Pohl U, Staszewski O, Korshunov A, Stein M, Wongsurawat T, Cheunsuacchon P, Sathornsumetee S, Koelsche C, Turner C, Le Rhun E, Mühlebner A, Schucht P, Özduman K, Ono T, Shimizu H, Prinz M, Acker T, Herold-Mende C, Kessler T, Wick W, Capper D, Wesseling P, Sahm F, von Deimling A, Hartmann C, and Reuss DE
- Subjects
- Adult, Aged, Brain Neoplasms genetics, Female, Humans, Male, Middle Aged, Mutation, Oligodendroglioma genetics, Sarcoma genetics, Brain Neoplasms pathology, Isocitrate Dehydrogenase genetics, Oligodendroglioma pathology, Sarcoma pathology
- Abstract
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., (© 2021. The Author(s).)
- Published
- 2022
- Full Text
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5. Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1.
- Author
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Suwala AK, Stichel D, Schrimpf D, Maas SLN, Sill M, Dohmen H, Banan R, Reinhardt A, Sievers P, Hinz F, Blattner-Johnson M, Hartmann C, Schweizer L, Boldt HB, Kristensen BW, Schittenhelm J, Wood MD, Chotard G, Bjergvig R, Das A, Tabori U, Hasselblatt M, Korshunov A, Abdullaev Z, Quezado M, Aldape K, Harter PN, Snuderl M, Hench J, Frank S, Acker T, Brandner S, Winkler F, Wesseling P, Pfister SM, Reuss DE, Wick W, von Deimling A, Jones DTW, and Sahm F
- Subjects
- Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 7 genetics, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA Copy Number Variations, Female, Gene Deletion, Glial Fibrillary Acidic Protein biosynthesis, Glial Fibrillary Acidic Protein genetics, Humans, Male, Middle Aged, Brain Neoplasms genetics, Brain Neoplasms pathology, DNA Methylation, Glioblastoma genetics, Glioblastoma pathology, Neuroectodermal Tumors, Primitive genetics, Neuroectodermal Tumors, Primitive pathology, PTEN Phosphohydrolase genetics, Retinoblastoma Binding Proteins genetics, Tumor Suppressor Protein p53 genetics, Ubiquitin-Protein Ligases genetics
- Abstract
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.
- Published
- 2021
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6. Neurofibromatosis type 2 predisposes to ependymomas of various localization, histology, and molecular subtype.
- Author
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Kresbach C, Dorostkar MM, Suwala AK, Wefers AK, Schweizer L, Engertsberger L, Bison B, Mynarek M, Kloth-Stachnau K, Spohn M, von Deimling A, Benesch M, Hagel C, Mautner VF, Rutkowski S, and Schüller U
- Subjects
- Adolescent, Adult, Child, Child, Preschool, DNA Methylation genetics, Female, Genes, Neurofibromatosis 2, Humans, Magnetic Resonance Imaging, Male, Mutation, Central Nervous System Neoplasms diagnostic imaging, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms pathology, Ependymoma diagnostic imaging, Ependymoma genetics, Ependymoma pathology, Neurofibromatosis 2 complications, Neurofibromatosis 2 genetics, Neurofibromatosis 2 pathology
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- 2021
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7. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis.
- Author
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Suwala AK, Stichel D, Schrimpf D, Kloor M, Wefers AK, Reinhardt A, Maas SLN, Kratz CP, Schweizer L, Hasselblatt M, Snuderl M, Abedalthagafi MSJ, Abdullaev Z, Monoranu CM, Bergmann M, Pekrun A, Freyschlag C, Aronica E, Kramm CM, Hinz F, Sievers P, Korshunov A, Kool M, Pfister SM, Sturm D, Jones DTW, Wick W, Unterberg A, Hartmann C, Dodgshun A, Tabori U, Wesseling P, Sahm F, von Deimling A, and Reuss DE
- Subjects
- Adolescent, Adult, Astrocytoma diagnosis, Brain Neoplasms diagnosis, Child, DNA Methylation, Female, Gene Dosage, Gene Expression Regulation, Neoplastic genetics, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Microsatellite Instability, Mutation genetics, Neoplasm Recurrence, Local, Prognosis, Signal Transduction genetics, Survival Analysis, X-linked Nuclear Protein genetics, Young Adult, Astrocytoma genetics, Brain Neoplasms genetics, DNA Mismatch Repair genetics, Isocitrate Dehydrogenase genetics
- Abstract
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.
- Published
- 2021
- Full Text
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