scholarly journals MBRS-38. MOLECULAR CLASSIFICATION AND CLINICAL CHARACTERISTICS OF 236 MEDULLOBLASTOMAS IN JAPAN

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii404-iii405
Author(s):  
Yonehiro Kanemura ◽  
Tomoko Shofuda ◽  
Ema Yoshioka ◽  
Daisuke Kanematsu ◽  
Koichi Ichimura ◽  
...  

Abstract Recent intensive genomic and molecular biological analyses have made a consensus that medulloblastomas (MBs) are at least classified into four core subgroups, and the new 2016 WHO brain tumor classification has introduced the classification of MBs genetically defined in addition to classical histopathological diagnosis. To establish a nationwide network of a molecular diagnosis system for pediatric brain tumors, the JPMNG co-organized by the Japan Society for Neuro-Oncology and the Japanese Society for Pediatric Neurosurgery have started the clinical researches in 2012, and we have summarized results of molecular analysis of Japanese MBs. Total 236 primary MBs have been subclassified by gene expression profile using the NanoString nCounter system or DNA methylation array, and their single nucleotide mutations and copy number aberrations have been also examined. Mean follow up time was 68.9 months. Proportion of four core subgroups were WNT (16.9%), SHH (25.4%), Group 3 (17.4%) and Group 4 (40.3%), respectively. In cases of less than 3 years old, no WNT have been found and 63.2% cases were SHH. In cases between 3 to 17 years old, Group 4 is the most (47%), and these trends is almost consistent with published references. TP53 mutations were identified in 23.3% of SHH, and they were significantly poor prognosis. Metastatic or MYC gain Group 3 MBs were poor prognosis, while Group 4 MBs with loss of chromosome 11 or whole chromosomal aberration were good prognosis. These findings reveal molecular properties of Japanese MBs and will contribute to develop new therapeutic strategies.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3691-3691 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Mohamed Elhamri ◽  
Jeremy Monfray ◽  
Helene Labussiere-Wallet ◽  
...  

Abstract We evaluated in this study the therapeutic management of all newly diagnosed acute myeloid leukemia (AML) patients followed in our center between July 2007 and September 2013, after stratification on age, prognostic factors, whether they were candidate to allogeneic hematopoietic stem cell transplantation (allo-HSCT), transplanted or not with the evaluation of each therapeutic strategy and its impact on overall survival. A total of 572 consecutive newly diagnosed AML patients were included; there were 311 (54%) males and 261 females with a median age of 63 years (range: 20-92), 406 (71%) were de novo AML and 166 (29%) secondary AML. Complete cytogenetic and molecular biology data were collected for all patients and prognosis was differentiated according to the European LeukemiaNet classification (Dohner et al. Blood 2010). Accordingly, 335 (59%) patients were unfavorable, 83 (15%) favorable, 48 (8%) intermediate I and 106 (18%) were in intermediate II category. Following the Acute Leukemia French Association (ALFA) guidelines for allo-HSCT in AML, patients with intermediate II and unfavorable prognosis ≤ 65 years should receive intensive chemotherapy followed by allo-HSCT in the presence of related or unrelated HSCT donors. We divided the population into two sub-populations, the first was considered as “young” with age ≤ 65 years (N=318, 56%) and the second considered as “old” with age > 65 years (N=254, 44%). In the young population, there was 4 groups, group 1: patients with good prognosis (favorable/intermediate1) who received intensive chemotherapy within or according to ALFA protocols (N=105, median age= 47 years); group 2: patients with poor prognosis (intermediate2 /unfavorable) who received intensive chemotherapy within or according to ALFA protocols followed by allo-HSCT (N=126, median age= 50 years), group 3: patients with poor prognosis who received only intensive chemotherapy without allo-HSCT (N=69, median age= 57 years), and group 4: patients with poor prognosis who could not be treated due to early death (N=18). In the old population we distinguished, group 1: patients with good prognosis who received moderate intensity chemotherapy within or according to ALFA protocols (N=25, median age=73 years); group 2: patients with poor prognosis who received azacitidine (N=25, median age=76 years), group 3: patients with poor prognosis who received moderate intensity chemotherapy (N=89, median age=76 years), group 4: patients with poor prognosis who received low dose Ara-C (N=28, median age=76 years), group 5: patients with poor prognosis who received other treatment (N=38, median age=77 years) and finally group 6: patients with poor prognosis considered as palliative or who did not receive any treatment (N=49, median age=77 years). After a median follow-up of 34 months (range: 4-77) for surviving patients, the 2-years probability of overall survival (OS) in the “young” population for groups 1,2,3 and 4 was 84%, 56%, 31% and 0% respectively; and in the “old” group it was 71%, 37%, 31%, 5%, 21% and 0% for groups 1,2,3,4,5 and 6 respectively (figure). We showed that newly diagnosed AML patients with good prognosis all ages included could achieve very good survival rates after intensive chemotherapy; allo-HSCT after induction chemotherapy remains the best therapeutic option for fit patients with poor prognosis while the same fit patients with no donor have significantly lower survival (p<0.001) and for whom allo-HSCT could be proposed by using haploidentical donors in case of cord blood or unrelated donors absence. Interestingly, in the “old” population, we showed that poor prognosis patients receiving azacytidine had a significantly better survival compared to those receiving low dose Ara-C (p=0.015), with a comparable outcome to those receiving induction chemotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii389-iii389
Author(s):  
Rahul Kumar ◽  
Maximilian Deng ◽  
Kyle Smith ◽  
Anthony Liu ◽  
Girish Dhall ◽  
...  

Abstract INTRODUCTION The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value &lt; 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.


2021 ◽  
Vol 39 (7) ◽  
pp. 807-821
Author(s):  
Rahul Kumar ◽  
Kyle S. Smith ◽  
Maximilian Deng ◽  
Colt Terhune ◽  
Giles W. Robinson ◽  
...  

PURPOSE We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.


2018 ◽  
Vol 138 (2) ◽  
pp. 231-240 ◽  
Author(s):  
Maria Łastowska ◽  
Joanna Trubicka ◽  
Magdalena Niemira ◽  
Magdalena Paczkowska-Abdulsalam ◽  
Agnieszka Karkucińska-Więckowska ◽  
...  
Keyword(s):  
Group 4 ◽  

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii391-iii391
Author(s):  
Sarah Leary ◽  
Roger Packer ◽  
Alok Jaju ◽  
Linda Heier ◽  
Peter Burger ◽  
...  

Abstract BACKGROUND Metastasis, residual disease, and diffuse anaplasia are high-risk features in medulloblastoma. METHODS This was a randomized phase 3 study. Patients age 3–21 years with high-risk medulloblastoma received (+/-) daily carboplatin with 36Gy craniospinal radiation and weekly Vincristine followed by six cycles of maintenance chemotherapy with Cisplatin, Cyclophosphamide and Vincristine (+/) 12 cycles of isotretinoin during and following maintenance. The primary endpoint was event-free survival, with exact log-rank test to compare arms. Retrospective molecular analysis included DNA methylation and exome sequencing. RESULTS Of 294 medulloblastoma patients enrolled, 261 were eligible by central review of radiology and pathology, median age 8.6 years (range 3.3–21.2), 70% male, 189 (72%) with metastatic disease, 58 (22%) with diffuse anaplasia, 14 (5%) with &gt;1.5cm2 residual disease. The 5-year EFS and OS for all subjects was 63%+4 and 73%+3, respectively. Isotretinoin randomization was closed due to futility. 5-year EFS was 66 + 5 with carboplatin versus 59 + 5 without (p=0.11), with effect exclusively observed in Group 3 subtype: 73%+8 with carboplatin versus 54%+9 without (p&lt;0.05). Overall survival differed by molecular subgroup (p=0.006): WNT 100%, SHH 54%+11, Group 3 74%+6, Group 4 77%+5 at 5 years. MYC amplification or isochromosome 17 were unfavorable in Group 3 (p=0.029). Chromosome 11 loss or chromosome 17 gain were favorable in group 4 (p&lt;0.001). No survival difference was observed with TP53 mutation in SHH subtype in this high-risk cohort. CONCLUSIONS Therapy intensification with carboplatin improved survival for high-risk group 3 medulloblastoma. These findings further support an integrated clinical and molecular risk stratification for medulloblastoma.


2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i11-i11
Author(s):  
Jack Goddard ◽  
Jemma Castle ◽  
Emily Southworth ◽  
Stephen Crosier ◽  
Idoia Martin-Guerrero ◽  
...  

Abstract Introduction Medulloblastoma (MB) is the most common malignant brain tumour in children. The most frequent molecular subgroup, Group 4 (MBGrp4) accounts for ~35/40% of cases, however it has the least understood underlying biology. Clinical outcomes are heterogeneous in MBGrp4 and are not accounted for by established clinico-pathological risk factors. There is now a requirement for a comprehensive study of MBGrp4, considering established clinico-pathological features and novel molecular biomarkers to enhance risk-stratification and identify novel therapeutic targets. Methods A clinically-annotated, retrospective MBGrp4 discovery cohort (n = 420) was generated from UK CCLG institutions, collaborating European centres and SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Contemporary, multi-omics profiling was performed. Focal and arm level copy number aberrations (CNAs) were determined from molecular inversion probe (MIP) or DNA methylation array which additionally provided next generation non-WNT/non-SHH (Grp3/Grp4) subtype classifications. Targeted next-generation DNA sequencing was performed to overlay the mutational landscape. Survival modelling was carried out with patients &gt;3 years old who received craniospinal irradiation. Results MBGrp4 subtypes were assigned to 88% of tumours with available data. Subtype VIII was strongly associated with i17q (p&lt;0.0001). The favourable-risk cytogenetic signature (2 or 3 of; chromosome 7 gain, chromosome 8 loss and/or chromosome 11 loss) associated with both subtypes VI and VII (p&lt;0.0001). MYCN amplifications were strongly associated with subtype V (p&lt;0.0001) in addition to 16q loss (p&lt;0.0001). The high-risk CNA group was enriched for mutations in genes involved in chromatin remodelling (p&lt;0.0001). Risk factors were identified from multivariate survival modelling. Subtype and CNA groups contributed to improved risk-stratification models that outperformed current clinical schemes. Conclusion Comprehensive genetic and epigenetic profiling in this large retrospective cohort has improved our understanding of the molecular and clinical heterogeneity within MBGrp4. Incorporation of molecular biomarkers improved risk-stratification for MBGrp4.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii391-iii391
Author(s):  
Jeff Michalski ◽  
Paul Northcott ◽  
Yimei Li ◽  
Catherine Billups ◽  
Kyle Smith ◽  
...  

Abstract The COG conducted a randomized trial for average-risk medulloblastoma (AR-MB). Patients age 3–21 years were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT) after receiving CSI. Patients age 3–7 years were also randomized to standard dose CSI (23.4Gy, SDCSI) or low dose CSI (18Gy, LDCSI). 464 evaluable patients were available to compare PFRT vs. IFRT and 226 for SDCSI vs. LDCSI. 380 cases had sufficient tissue for DNA methylation-based molecular classification: 362 confirmed medulloblastoma; 6 non-medulloblastoma; 12 inconclusive. Molecular subgrouping confirmed the following representation amongst the evaluable cohort: 156 Group 4 (43.1%), 76 Group 3 (21.0%), 66 SHH (18.2%), 64 WNT (17.7%). Five-year event-free survival (EFS) estimates were 82.5±2.7% and 80.5±2.7% for IFRT and PFRT, respectively (p=0.44). Five-year EFS estimates were 71.4±4.4% and 82.9±3.7% for LDCSI and SDCSI, respectively (p=0.028). EFS distributions differed significantly by subgroup (p&lt;0.0001). Group 3 had the worst outcome, while WNT had the best outcome. There was a significant difference in EFS by RT group among SHH patients; SHH patients receiving IFRT arm had better EFS compared to PFRT (p=0.018). There was a significant difference in EFS distributions by CSI group in Group 4 patients; young Group 4 patients treated with SDCSI had better EFS compared to LDCSI (p=0.047). As previously reported, IFRT is noninferior to PFRT in all patients with AR-MB but LDCSI is worse than SDCSI in younger children. Significant differences in outcome by study randomization and molecular subgroup are observed.


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii358-iii359
Author(s):  
Ioan Paul Voicu ◽  
Piero Chiacchiaretta ◽  
Massimo Caulo ◽  
Evelina Miele ◽  
Alessia Carboni ◽  
...  

Abstract PURPOSE Medulloblastoma (MB) is a complex pathology. Four molecular subgroups have been unveiled (Wingless-WNT, Sonic Hedgehog-SHH, Group 3-G3 and Group 4-G4), characterized by significant differences in patient clinical outcome. We investigated the utility of a radiomic analysis to predict molecular subgroups in patients with MB. MATERIALS AND METHODS We retrospectively evaluated 42 patients with histological diagnosis of MB, known molecular subgroup, and diagnostic MRI scan performed in our Institution on a 3 Tesla magnet. For each patient, FLAIR, ADC, T2 and contrast-enhanced MPRAGE sequences were analysed. Solid tumor volumes were segmented semiautomatically. 107 features were extracted for each sequence (Pyradiomics, Python). Features were tested for stability against labelling variations, selecting those presenting Intraclass Correlation Coefficient (ICC)&gt;0.9 across all labelling variations and all sequences. Among the remaining features, relevant features were selected with an all-relevant wrapper algorithm (Boruta, R). Remaining features were used to predict MB subgroup with a Random Forest algorithm(R). The most relevant features were ranked based on Gini index (R). RESULTS 83/107 features presented ICC &gt;0.9 for all sequences. Boruta selected 10 features. Classification analysis yielded an out-of-bag (OOB) error rate of 0.6%, (99.4% accuracy). The most relevant features for classification were “simple” first-order features such as volume, major axis or shape. CONCLUSION This radiomic study yielded robust features, which showed high accuracy in predicting the molecular MB subgroups. Random forest algorithms are ideal for multiclass classification (eg. MB subgroups) and are intrinsically suited against overfitting. The most relevant for molecular classification were first-order features.


2014 ◽  
Vol 32 (9) ◽  
pp. 886-896 ◽  
Author(s):  
David J.H. Shih ◽  
Paul A. Northcott ◽  
Marc Remke ◽  
Andrey Korshunov ◽  
Vijay Ramaswamy ◽  
...  

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.


2021 ◽  
Vol 11 ◽  
Author(s):  
Chaoying Qin ◽  
Yimin Pan ◽  
Yuzhe Li ◽  
Yue Li ◽  
Wenyong Long ◽  
...  

Medulloblastoma (MB) is a highly heterogeneous and one of the most malignant pediatric brain tumors, comprising four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. Group 3 MB has the worst prognosis of all MBs. However, the molecular and cellular mechanisms driving the maintenance of malignancy are poorly understood. Here, we employed high-throughput single-cell and bulk RNA sequencing to identify novel molecular features of Group 3 MB, and found that a specific cell cluster displayed a highly malignant phenotype. Then, we identified the glutamate receptor metabotropic 8 (GRM8), and AP-1 complex subunit sigma-2 (AP1S2) genes as two critical markers of Group 3 MB, corresponding to its poor prognosis. Information on 33 clinical cases was further utilized for validation. Meanwhile, a global map of the molecular cascade downstream of the MYC oncogene in Group 3 MB was also delineated using single-cell RNA sequencing. Our data yields new insights into Group 3 MB molecular characteristics and provides novel therapeutic targets for this relentless disease.


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