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  • Oxford University Press (OUP)  (16)
  • Frank, Stephan  (16)
  • 1
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    Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. 10 ( 2022-10-03), p. 1689-1699
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. 10 ( 2022-10-03), p. 1689-1699
    Abstract: Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients’ clinical course are unknown. Methods We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPE-B, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. Results MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (P = 3.4e-06). Conclusions We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac088
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
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    EPEN-06. Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i39-i39
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i39-i39
    Abstract: Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients’ clinical course are unknown. We assembled a cohort of 185 tumors classified as MPE based on DNA methylation from pediatric, adolescent, and adult patients. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPEB, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. Tumors in the methylation class MPE were histologically diagnosed as WHO grade I (59%), WHO grade II (37%), or WHO grade III tumors (4%). 75/77 analyzed tumors expressed HOXB13, which is a diagnostic feature not detected in other spinal ependymal tumors. Based on DNA methylation, our series split into two subtypes. MPE-A occurred in younger patients (median age 27 vs. 45 years, p=7.3e-05). They were enriched with WHO grade I tumors and associated with papillary morphology and MGMT promoter hypermethylation (all p & lt;0.001). MPE-B included most tumors initially diagnosed as WHO grade II and cases with tanycytic morphology. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. 15/30 MPE-A could not be totally resected compared to 1/58 MPE-B (p=6.3e-08), and progression-free survival was significantly better for MPE-B (p=3.4e-06, 10-year relapse rate 33% vs. 85%). We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.143
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    PATH-16. HISTOPATHOLOGICAL EPENDYMOMA VARIANTS ARE ASSOCIATED WITH DISTINCT CLINICAL PARAMETERS AND DNA METHYLATION PATTERNS
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi146-vi146
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi146-vi146
    Abstract: According to the current WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas and RELA-fusion positive ependymoma (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e. the clear-cell, papillary, and tanycytic ependymoma. In parallel to this WHO classification scheme, DNA methylation patterns can distinguish nine distinct molecular ependymoma subgroups, some of which tightly overlap with certain histopathological subgroups, e.g. subependyomas or myxopapillary ependymomas. Since very little is known about the molecular background of histological classic ependymoma variants, we analyzed histomorphology, clinical parameters and global DNA methylation patterns of diagnosed tanycytic ependymomas (n=12), clear-cell ependymomas (n=14) and papillary ependymomas (n=19). Surprisingly, up to 42% of these variants did not match to ependymomas using a previously published DNA methylation-based classifier for brain tumors. Among the tumors with a match to one of the nine known ependymoma methylation classes, tanycytic ependymomas were predominantly located in the spine, but showed diverse molecular methylation patterns. Most clear-cell ependymomas showed a common histomorphology, were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas showed a “papillary”, “trabecular” or “pseudo-papillary” growth pattern. Interestingly, a true papillary growth pattern was strongly associated with the molecular class B of posterior fossa ependymoma (PFB), but tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Our results show that the diagnosis of classic histological ependymoma variants can be challenging. While clear-cell and papillary ependymomas harbor common molecular features, tanycytic ependymoma may not represent a molecularly distinct subgroup.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.612
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 4
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    Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology ( 2023-06-28)
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), ( 2023-06-28)
    Abstract: The prognosis for Li–Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. Methods In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. Results The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup “SHH_3” (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). Conclusions LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad114
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 5
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    MEDB-14. Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i107-i107
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i107-i107
    Abstract: PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes. PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated. RESULTS: All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p & lt;0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients. CONCLUSIONS: Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.389
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
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    EPEN-27. Epigenetic dissection of spinal ependymomas (SP-EPN) separates tumors with and without NF2 mutation
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i44-i45
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i44-i45
    Abstract: Ependymomas encompass multiple, clinically relevant tumor types based on localization, genetic alterations, and epigenetic and transcriptomic profiles. Tumors belonging to the methylation class of spinal ependymoma (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, molecular data of SP-EPN are scarce, and clear treatment recommendations are lacking. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations. Yet, it remains unclear whether SP-EPN with germline or sporadic NF2 mutations or with NF2 wild type status differ clinically or molecularly. To provide a comprehensive molecular profile of SP-EPN, we integrated epigenetic, genomic, transcriptomic, and histological analyses of up to 237 cases. Clustering of methylation data revealed two distinct molecular SP-EPN subtypes. The distribution of NF2 mutated cases differed significantly across these subtypes (p & lt;0.0001): The vast majority of tumors harboring either a previously known NF2 germline mutation or a sporadic mutation were assigned to subtypes A, whereas subtype B tumors mainly contained NF2 wild type sequences. In addition, subtype A tumors showed a lower frequency of MGMT promoter methylation (p= 0.018) and contained almost all pediatric patients of the cohort. Whole-exome sequencing (30 cases) identified numerous mutations in NF2 wild type and mutated tumors. Mutated genes in NF2 wild type tumors were enriched for genes associated with cell cycle and cytoskeleton. RNA sequencing revealed two distinct transcriptional groups with upregulation of proliferative genes in one group and upregulation of cilial genes in the other group. The molecular subtypes displayed subtle, but significant differences in the appearance of histopathological characteristics, such as surfaces, inflammation, and hyalinized vessels. Investigation of clinical parameters is ongoing and will complete the picture of SP-EPN heterogeneity as an important basis for future clinical decision-making.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.163
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    MDB-15. CLINICAL CHARACTERISTICS AND OUTCOME OF CHILDHOOD LI-FRAUMENI SYNDROME MEDULLOBLASTOMA PATIENTS
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i64-i65
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i64-i65
    Abstract: Patients with Li-Fraumeni syndrome (LFS) who develop medulloblastoma (MB) have a very poor prognosis. The development of novel therapeutic strategies is challenged by the lack of clinical data for this patient group. We here present clinical and molecular data on a retrospective cohort of pediatric patients with LFS-associated MB. This is an international, retrospective, multicenter cohort study. Patients with LFS-associated MB under 21 years and class 5 (pathogenic) or class 4 (likely pathogenic) constitutional TP53 variants were included. We evaluated TP53 mutation status (constitutional and somatic), DNA methylation subgroup, treatment modalities, event-free (EFS) and overall survival (OS), patterns of recurrence, as well as occurrence of secondary neoplasms. Forty-seven individuals with LFS-associated MB were included. MBs were classified mainly as Sonic Hedgehog (SHH) group (87%). TP53 variants were classified as class 5 (70%) and class 4 (30%). The majority (74%) of TP53 variants represented missense variants. The 2-year (y-) EFS and -OS were 33% and 53%, respectively. A significantly better outcome was seen in patients who received post-operative radiotherapy (RT) (2y-EFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-EFS: 24%, 2y-OS: 48%) compared with patients who received no RT (2y-EFS: n.a., 2y-OS: 25%). No significantly different outcomes were seen between patients treated either according to protocols including high-intensity chemotherapy or receiving only maintenance-type chemotherapy (2y-EFS: 42% and 31%, 2y-OS: 68% and 53%, respectively). Patients with LFS-associated MB have a dismal prognosis. Use of RT in LFS-associated MB significantly increased survival rates in the presented cohort, but choice of chemotherapy regimen did not influence their clinical outcome. To improve the outcome of patients with LFS-associated MB, prospective collection of clinical data and development of novel treatments are required.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.248
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 8
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    PATH-39. INTEGRATED MOLECULAR-MORPHOLOGICAL MENINGIOMA CLASSIFICATION: A MULTICENTER RETROSPECTIVE ANALYSIS, RETRO- AND PROSPECTIVELY VALIDATED
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi123-vi124
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi123-vi124
    Abstract: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from cases with benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for the individual patient is of pivotal importance in clinical management. However, only biomarkers for highly aggressive tumors are established at present (CDKN2A/B and TERT), while no molecularly-based stratification exists for the broad spectrum of low- and intermediate-risk meningioma patients. PATIENTS AND METHODS DNA methylation data and copy-number information were generated for 3,031 meningiomas of 2,868 individual patients, with mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNV), mutations and WHO grading were comparatively analyzed. Prediction power for outcome of these parameters was assessed in an initial retrospective cohort of 514 patients, and validated on a retrospective cohort of 184, and on a prospective cohort of 287 multi-center cases, respectively. RESULTS Both CNV and methylation family- (MF)-based subgrouping independently resulted in an increase in prediction accuracy of risk of recurrence compared to the WHO classification (c-indexes WHO 2016, CNV, and MF 0.699, 0.706 and 0.721, respectively). Merging all independently powerful risk stratification approaches into an integrated molecular-morphological score resulted in a further, substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference p=0.005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (HR 4.56 [2.97;7.00], 4.34 [2.48;7.57] and 3.34 [1.28; 8.72] for discovery, retrospective, and prospective validation cohort, respectively). CONCLUSIONS Merging these layers of histological and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision-making for meningioma patients on the basis of robust outcome prediction.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.491
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 9
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    PATH-04. Array-based global DNA Methylation profiling of mouse brain tumors allows comparison to human tumors
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i158-i159
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i158-i159
    Abstract: The classification of human brain tumors by global DNA methylation profiling has become an essential part of modern integrated neuropathological diagnostics. It has proven to reliably identify known and novel brain tumor (sub-)types that are biologically and clinically distinct. Therefore, this technique has critically improved diagnostic accuracy and risk stratification of brain tumor patients. Although indispensable for the understanding of tumor biology and for preclinical drug trials, the comparison of genetically engineered mouse models to human brain tumors is still difficult. The assessment of tumor morphology only provides an approximate picture, and transcriptomic data from human brain tumors are sparse and suffer from platform-related technical incomparability. Here, we show array-based DNA methylation profiling of well-established murine brain tumors, such as Wnt and Shh medulloblastoma, YAP and RELA ependymoma, ETMR, and AT/RT. Similar to human brain tumors, unbiased clustering methods revealed distinct methylation profiles and mean methylation levels for mouse brain tumors types. Analyses were possible for fresh-frozen as well as for paraffin-embedded tissue, and copy number alterations could be inferred from methylation profiles. Most importantly, first results suggest that inter-species comparisons allow the classification of brain tumors from known or novel mouse models based on the constantly growing spectrum of human brain tumor types and subtypes with hundreds of thousands of available datasets. As an example, upon DNA methylation profiling, cerebellar tumors arising in Math1-cre::SmoM2Fl/+ mice display the highest similarity to human SHH medulloblastoma when compared to multiple human brain tumor entities including WNT and Non-WNT/Non-SHH medulloblastoma. These results suggest that global DNA methylation profiling may add another very important level of information to the characterization of genetically engineered mouse models.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.588
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 10
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    CBMT-27. PROTEOMIC MAP OF GLIOMA BIOPSIES REVEALS FUNCTIONAL DEFECTS IN ENDOCYTOSIS
    Oxford University Press (OUP) ; 2018
    In:  Neuro-Oncology Vol. 20, No. suppl_6 ( 2018-11-05), p. vi38-vi38
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_6 ( 2018-11-05), p. vi38-vi38
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noy148.146
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
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