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  • Pfister, Stefan M  (53)
  • 1
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    ATRT-08. SMARCB1- and SMARCA4-deficient malignant brain tumors with complex copy number alterations and TP53 mutations may represent the first clinical manifestation of Li-Fraumeni syndrome
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i4-i4
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i4-i4
    Abstract: Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising in other central nervous system tumors have been reported. Malignant gliomas, IDH-wildtype, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about loss of SMARCB1 or SMARCA4 protein expression in this context. Here we report two children, in whom malignant supratentorial brain tumors with SMARCB1-deficiency, complex copy number alterations and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germ line. Screening of the molecularneuropathology.org data set for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4-deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1- or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.007
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
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    ETMR-06. Molecular and clinical characteristics of CNS tumors with BCOR(L1 ) fusion/internal tandem duplication
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i50-i50
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i50-i50
    Abstract: Central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR-ITD) have recently been introduced in the 5th edition of the WHO classification of CNS tumors, however, their molecular makeup and clinical characteristics remain widely enigmatic. This is further complicated by the recent discovery of tumors characterized by gene fusions involving BCOR or its homologue BCORL1. We identified a cohort of 206 BCOR altered CNS tumors via DNA methylation profiling and conducted in-depth molecular and clinical characterization in an international effort. By performing t-SNE clustering analysis we found that BCOR-fusion tumors form a distinct cluster (n=61), adjacent to BCOR-ITD cases (n=145). The identified fusion partners of BCOR(L1) included EP300 (n=20), CREBBP (n=5), and NUTM2HP (n=1). Notably, three cases within the BCOR-ITD cluster harbored a c-terminal intragenic deletion within BCOR. With respect to clinical characteristics gender ratio was balanced in BCOR-fusion cases (m/f, 1.1), whereas predominance of male patients was observed in the BCOR-ITD group (m/f, 1.5). Moreover, age at diagnosis of BCOR-fusion patients was higher as compared to BCOR-ITD cases (15 vs 4.5 years). Interestingly, BCOR-fusion tumors were exclusively found in the supratentorial region being originally diagnosed as ependymomas or gliomas whereas BCOR-ITD emerged across the entire CNS with diverse original diagnoses. 8% of BCOR-ITD and none of BCOR-fusion cases were disseminated at diagnosis. In line with this observation, 40% of first relapses within the BCOR-ITD group were metastatic which was less frequent in BCOR-fusion tumors. Survival estimates demonstrated no differences, generally showing short median PFS (BCOR-fusion, 2 years, n=15; BCOR-ITD, 1.8 years, n=55) and intermediate OS rates (BCOR-fusion, 6.8 years, n=18; BCOR-ITD 6.3 years, n=60). Further molecular and clinical characterization is ongoing potentially revealing first therapeutic leads for these highly aggressive CNS tumor types.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.184
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    RARE-15. Astroblastoma, MN1 altered comprises two molecularly and clinically distinct subgroups defined by the fusion partners BEND2 and CXXC5
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i12-i13
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i12-i13
    Abstract: In the recent 5th edition of the WHO classification of CNS tumors, ‘Astroblastoma, MN1 altered’ is recognized a distinct brain tumor type, occurring in children and young adults. Due to its rarity and novelty, little is known about clinical and molecular traits. Therefore, we initiated an international effort and collected tissue samples, clinical and molecular data from 176 patients with Astroblastoma, MN1 altered, identified by their distinct DNA methylation profiles. DNA methylation-based t-SNE clustering analyses revealed that Astroblastoma, MN1 altered tumors form one distinct main cluster (n=158) showing MN1:BEND2 and single cases with EWSR1:BEND2 fusions and a further adjacent, but distinct smaller cluster (n=18) mostly defined by MN1:CXXC5 fusions. Both fusion partner-defined groups show a median age of 12 years but distinct copy-number aberrations, characteristically a gain of chromosome 5 in one third of the CXXC5-fused group and a loss of chromosome 16q in one third of BEND2-fused cases. As previously reported, a vast majority of Astroblastoma, MN1 altered patients are female, which we confirm for the BEND2-fused group (85%). The CXXC5-fused group, however, shows 75% male patients. Interestingly, 9/10 tumors of the few male patients observed in the BEND2-fused group were all located infratentorially or in the spinal cord, whereas almost all female cases show a supratentorial location (85/87). Histologically, the BEND2-fused group was primarily reported as Astroblastoma (39%), whereas in the CXXC5-fused cases, 31% CNS-PNET and only 8% Astroblastoma histologies were originally assigned. Preliminary clinical analyses showed that the BEND2-fused group has a relatively good 5/10-year OS of 97%/89%, but a less favorable 5/10-year PFS of 48%/35%, in line with previous studies. Patients showing CXXC5-fused tumors (n=8) indicated 5/10-year OS and PFS rates of 83%/83% and 60%/60%, respectively. Additional survival and molecular analyses are being conducted to further characterize Astroblastoma, MN1 altered tumors and its molecular subgroups.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.040
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 4
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    Analysis of recurrence probability following radiotherapy in patients with CNS WHO grade 2 meningioma using integrated molecular-morphologic classification
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Advances Vol. 5, No. 1 ( 2023-01-01)
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    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 5, No. 1 ( 2023-01-01)
    Abstract: The current World Health Organization (WHO) classification of brain tumors distinguishes 3 malignancy grades in meningiomas, with increasing risk of recurrence from CNS WHO grades 1 to 3. Radiotherapy is recommended by current EANO guidelines for patients not safely amenable to surgery or after incomplete resection in higher grades. Despite adequately predicting recurrence probability for the majority of CNS WHO grade 2 meningioma patients, a considerable subset of patients demonstrates an unexpectedly early tumor recurrence following radiotherapy. Methods A retrospective cohort of 44 patients with CNS WHO grade 2 meningiomas were stratified into 3 risk groups (low, intermediate, and high) using an integrated morphological, CNV- and methylation family-based classification. Local progression-free survival (lPFS) following radiotherapy (RT) was analyzed and total dose of radiation was correlated with survival outcome. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities were further assessed. Results Risk stratification of CNS WHO grade 2 meningioma into integrated risk groups demonstrated a significant difference in 3-year lPFS following radiotherapy between the molecular low- and high-risk groups. Recurrence pattern analysis revealed that 87.5 % of initial relapses occurred within the RT planning target volume or resection cavity. Conclusions Integrated risk scoring can identify CNS WHO grade 2 meningioma patients at risk or relapse and dissemination following radiotherapy. Therapeutic management of CNS WHO grade 2 meningiomas and future clinical trials should be adjusted according to the molecular risk-groups, and not rely on conventional CNS WHO grading alone.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdad059
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 5
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    PATH-04. AN ENHANCED AI-DRIVEN PLATFORM FOR PRECISION MOLECULAR BRAIN TUMOR DIANOSTICS
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii425-iii425
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii425-iii425
    Abstract: Tumors of the CNS represent one of the most complex groups of human cancer, with a vast number of different entities occurring across a spectrum of ages and anatomic locations. This heterogeneity makes accurate diagnosis challenging, with the current gold standard relying on multiple subjective elements. We recently proposed a classification algorithm based on tumor DNA methylation profiling as an objective way to assign samples to over 80 distinct molecular classes. Here we present a substantial update to our machine learning-based algorithm, with more than 170 molecular classes now being represented amongst the 5,915 samples in our reference cohort. These new classes include further subclassification of known groups such as medulloblastoma and ependymoma, as well as multiple new molecular entities described here for the first time. A further improvement is the introduction of a more rationally layered output, making use of ‘families’ of closely-related molecular classes to improve the compatibility with the current WHO classification of CNS tumors. This approach is designed to increase the clinical relevance of the primary output, while also retaining the full information content from the random forest-driven classification. Benchmarking our new algorithm by cross-validation and on an independent validation cohort indicates a retention of the excellent accuracy of diagnosis (error-rate & lt; 4%), with a significant improvement in the proportion of confidently classifiable tumors compared with our previous tool. We believe that this approach, freely accessible through an online web portal, has the potential to enhance diagnostic precision and thereby support clinical care for brain tumor patients.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.640
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    LGG-11. BH3-MIMETICS TARGETING BCL-XL SELECTIVELY IMPACT THE SENESCENT COMPARTMENT OF PILOCYTIC ASTROCYTOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i33-i34
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i33-i34
    Abstract: Pilocytic astrocytoma (PA) is the most common brain tumor in children. Activation of the mitogen-activated protein kinase (MAPK) pathway is a hallmark of PA. Complete remission in non-resectable tumors is infrequently observed with current therapeutic approaches. Most PA tumors cells are in oncogene-induced senescence (OIS), which may explain the benign growth behavior of PAs but also account for resistance to therapy. Therefore, treatment of PA with senolytic agents such as BH3-mimetics is a promising new approach. Methods Three patient-derived PA cell lines, DKFZ-BT66, DKFZ-BT308 (both KIAA1549:BRAF-fusion positive) and DKFZ-BT314 (BRAF V600E-mutation positive) were used. Depending on inducible expression or repression of SV40 large T antigen all models can reflect both states of PA, proliferation and OIS. Cells in both states were treated with different BH3-mimetics. Inhibition of metabolic activity was measured after 72 hours. Target expression was assessed by RT-qPCR and Western blot. On-target activity of BH3-mimetics was determined by immunoprecipitation (IP) of Bcl-xL/BAK. Results BH3-mimetics with strong binding affinity for Bcl-xL (Navitoclax, A-1131852, A-1155463) showed selectivity for senescent cells in 2/3 models (DKFZ-BT66 and DKFZ-BT314) and acted in nanomolar ranges. IC50s for Navitoclax (Cmax 6600nM in patients) were 40nM (OIS) vs. 200nM (proliferation) and 170nM (OIS) vs. 3700nM (proliferation) in DKFZ-BT66 and DKFZ-BT314, respectively. Target engagement was evident in the Bcl-xL/BAK-IP, and target expression of Bcl-xL was similar in all models studied. The relative resistance of senescent DKFZ-BT308 despite on-target activity is currently being investigated. Conclusion Senolytic treatment of PA with BH3-mimetics targeting Bcl-xL is a promising new strategy directly targeting the major senescent part of the tumor in clinically archivable concentrations. However, our data suggests that not all PAs may respond to treatment. The analysis of comparative gene expression analysis and BH3-profiling is ongoing to define predictive biomarkers.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.135
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 7
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    MEDB-37. Chemotherapy response prediction by molecular risk factors in metastatic childhood medulloblastoma
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i113-i113
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i113-i113
    Abstract: BACKGROUND: Childhood metastatic medulloblastoma (MB) frequently receive postoperative chemotherapy (CT) before craniospinal irradiation. Some MB show stable (SD) or progressive disease (PD) upon CT. Identification of biomarkers for non-response might allow therapy-modifications. METHODS: Patients registered to the German HIT-MED database (2001–2019) were eligible if they were 4-21 years old at diagnosis of a M2/M3-metastasized MB, received therapy in analogy to the MET-HIT2000-AB4 protocol, had centrally reviewed response assessment after 2 cycles HIT-SKK-CT and DNA-methylation analysis was available. DNA-methylation-based tumor classification and whole chromosomal (WC) losses/gains were derived from DNA-methylation arrays. RESULTS: 51/163 (31.3%) patients (median age: 9.8±4.4 years, median follow-up: 6.2±4.0 years) presented SD/PD during/after HIT-SKK-CT and were classified as non-responder. Response to CT had high predictive value for PFS/OS (5-year PFS responder: 67.9±4.8 %, non-responder: 26.1±6.6%, p & lt;0.01 / 5-year OS responder: 80.0±4.2%, non-responder: 45.9±8.0%, p & lt;0.01). Patients with nonWNT/nonSHH-MB subtype II (response: 7/13), subtype III (response: 6/19) and/or MYC-amplification (n=27, overlap subtype II/III: n=11/8, response: 14/27) were less likely to respond, while all 6 of WNT, 8/9 SHH-TP53-wildtype and 1/1 SHH-TP53-mutant responded (Mann-Whitney-U-test p=0.04). Further, ≥2 WC losses/gains of chromosome 7/8/11 was associated with superior response (n=29/32, others: n=83/131, Mann-Whitney-U-test p & lt;0.01). We identified a very-high-risk-cohort (any two criteria of: & lt;2 WC losses/gains of chromosome 7/8/11, MYC-amplification, MB subtype II, III, V, or VIII, n=94), and a standard-risk-cohort (WNT or any ≥2 WC losses/gains of chromosome 7/8/11, n=37) with 40 vs. 8 % non-response and 44±5/60±5 vs. 79±7/87±6% 5-year PFS/OS (p & lt;0.01/p & lt;0.01), respectively. Non-response in n=32 non-VHR/non-SR-patients was 32% with a 5-years PFS/OS of 60±10/77±8%. CONCLUSION: Molecular information can be helpful to predict response to chemotherapy. Upon validation, this may contribute to improve treatment stratification in metastatic MB.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.411
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 8
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    PATH-13. Methylation analysis in the diagnosis of pediatric CNS tumors; a single center experience
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i161-i161
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i161-i161
    Abstract: BACKGROUND: Tumors of Central Nervous System (CNS) comprise major cause of cancer-related morbidity and mortality during childhood. Recent advances in genome and epigenome research allow for molecular classification of CNS tumors, treatment stratification and therapeutic target identification. In many countries, including Greece, this integrated diagnosis is not possible, yet, in a routine setting due to financial and infrastructural reasons. DESIGN/METHODS: We analyzed the results from the methylation profiling performed on tumor samples from newly diagnosed and selected retrospective patients followed in our unit. Analyses were performed through the PTT2.0 and MNP2.0 Studies, as part of a collaboration project between ACCC (Athens Cancer Comprehensive Center) and DKFZ (German Cancer Research Center). RESULTS: Methylation arrays from 50 patients (mean age: 8years, range: 0-17years) have been analyzed. High calibrated score ( & gt;0.9) was achieved in 38 patients (76%) and in 33 (86%) of these, the histological diagnosis matched the methylation class. The remaining 5 cases, diagnosed by the local pathologist as ganglioneuroma, primitive neuroectodermal tumor, anaplastic astrocytoma, pineoblastoma and oligodendroglioma, were classified according to the methylation profiling as dermatofibrosarcoma protuberans, medulloblastoma group 3, high-grade glioma H3.3G34mutant, high-grade neuroepithelial tumor with BCOR alteration and glioneuronal tumor, respectively. Only four cases had no match in the classifier, while seven cases received low score (0.5-0.8). In 6 out of the 7 cases with low score, the diagnosis was confirmed with the use either of the copy-number profile inferred from the methylation array or by additional testing for gene fusions and mutations. In 25 medulloblastomas, methylation profiling provided molecular classification, according to the 2021 WHO Classification. CONCLUSIONS: Our experience on the first 50 cases suggests that methylation array needs to be considered as an integral part of the diagnostic process of pediatric patients with CNS tumors and highlights the importance of international collaboration programs in pediatric neuro-oncology.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.597
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    HGG-61.Landscape of cancer predisposition in pediatric high-grade glioma
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i76-i76
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i76-i76
    Abstract: Current estimates indicate that approximately 8–10% of cancer incidence in young patients can be attributed to constitutional alterations in genes linked to tumor initiation. The rarity and highly heterogeneous nature of high-grade glioma (HGG) in children and adolescents requires coordinated efforts to capture the diversity of subtypes in a normal-tumor matched sequencing cohort. Combining sequencing data of two registries based at the Hopp Children's Cancer Center (KiTZ) Heidelberg (INFORM and MNP2.0) allowed us to investigate the landscape of constitutional alterations across 350 children with high-grade gliomas. Both cohorts independently showed a surprisingly high proportion of patients (17%) with constitutional pathogenic alteration variants in cancer predisposition genes (n=40/233 and 23/128). Our results confirm a high frequency of alterations affecting genes of the DNA mismatch repair (MMR) pathway in 44% of IDH-mutant tumors (n=12/27). Additionally, we observed an almost exclusive correlation of MSH6 constitutional variation and somatic mutation in the IDH1 gene (n=7/8). A hypermutator phenotype defined by a tumor mutational burden & gt;10 mutations/mb) was linked in 14/17 patients to a constitutional alteration in one of the following MMR genes: MLH1, MSH2, MSH6 or PMS2, with IDH-wildtype cases mostly classified as ‘RTK1 subtype’ by DNA methylation analysis. Constitutional alterations in TP53 were found in 5% of the total cohort. Furthermore, these tumors occurred exclusively in the group of H3-/IDH-wildtype glioblastoma (12%), and 8/18 tumors belong to the pedHGG_MYCN subgroup (conversely, this represents 40% of all ‘MYCN subtype’ patients, a highly significant enrichment over other subtypes (p & lt;0.001). The overall high percentage of constitutional alterations in pediatric HGG warrants human genetics counselling for all affected patients and their families. Additionally, the strong correlation of MSH6 and IDH mutations as well as Li-Fraumeni-Syndrome and MYCN positive signature should be further explored as this might open the avenue for much needed new therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.276
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 10
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    Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. 8 ( 2023-08-03), p. 1518-1529
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. 8 ( 2023-08-03), p. 1518-1529
    Abstract: The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse. Methods One hundred and forty-four patients with DMB (n = 99) or MBEN (n = 45) aged & lt;5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients were evaluated. Results Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs. 93% [MBEN] ). Patients aged & gt;3 years were associated with more unfavorable 5y-PFS (47% [ & gt;3 years] vs. 85% [ & lt;1 year] vs. 84% [1–3 years] ). DNA methylation profiles available (n = 78) were reclassified according to the 2021 WHO classification into SHH-1 (n = 39), SHH-2 (n = 38), and SHH-3 (n = 1). Hierarchical clustering delineated 2 subgroups among SHH-2: SHH-2a (n = 19) and SHH-2b (n = 19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs. 83% [SHH-1] vs. 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using 2 independent cohorts (total n = 188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations. Conclusions These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with a higher risk of relapse.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad027
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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