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Journal of Clinical Oncology : Official... Mar 2021SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological...
PURPOSE
SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma.
PATIENTS AND METHODS
Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories.
RESULTS
Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( = .74) or when patients were stratified by clinical risk ( = .71). Mutations in (96%), (37%), and (24%) were most common in WNT tumors and (38%), (21%), and (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%).
CONCLUSION
These results establish a new risk stratification for future medulloblastoma trials.
Topics: Adolescent; Biomarkers, Tumor; Cerebellar Neoplasms; Child; Child, Preschool; DNA Methylation; DNA Mutational Analysis; Epigenome; Epigenomics; Female; High-Throughput Nucleotide Sequencing; Humans; Magnetic Resonance Imaging; Male; Medulloblastoma; Mutation; Predictive Value of Tests; Progression-Free Survival; Risk Assessment; Risk Factors; Time Factors; Young Adult
PubMed: 33405951
DOI: 10.1200/JCO.20.01372 -
Acta Neuropathologica Aug 2019In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with... (Meta-Analysis)
Meta-Analysis
In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.
Topics: Adolescent; Cerebellar Neoplasms; Child; Child, Preschool; DNA Methylation; DNA, Neoplasm; Female; Gene Expression Profiling; Genes, myc; Humans; Infant; Kaplan-Meier Estimate; Male; Medulloblastoma; Transcriptome
PubMed: 31076851
DOI: 10.1007/s00401-019-02020-0 -
Current Neurology and Neuroscience... Dec 2023Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma. (Review)
Review
PURPOSE OF REVIEW
Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma.
RECENT FINDINGS
The classic four subgroups have been reclassified and further subdivided based on new molecular findings. Research is revealing the cell origins of the different subtypes of medulloblastoma. There has been continued personalization of management based on molecular parameters. While many advances have been made in the knowledge base of this most common malignant pediatric brain tumor, there has not yet been translation into more effective therapies to prolong survival in all subgroups with the possible exception of children with group 3 disease. Quality of life remains a major challenge for long-term survivors.
Topics: Child; Humans; Medulloblastoma; Quality of Life; Brain Neoplasms; Cerebellar Neoplasms
PubMed: 37943476
DOI: 10.1007/s11910-023-01316-9 -
ESMO Open Aug 2021Medulloblastoma is a rare tumour in postpubertal patients and adults that is potentially curable. Several subgroups have been defined that are associated with clinical... (Review)
Review
Medulloblastoma is a rare tumour in postpubertal patients and adults that is potentially curable. Several subgroups have been defined that are associated with clinical features, have different prognoses, and in some cases offer personalized treatment options. In adults, the sonic hedgehog (SHH) subtype is the most common subtype, followed by the wingless (WNT) and group 4 subtypes. Multimodal therapies allow 5-year overall survival rates of up to 70%. However, in adults, therapeutic evidence from prospective randomized trials is largely lacking. Therefore, regardless of individual risk, most patients are currently treated uniformly with craniospinal chemoradiation with a boost to the tumour bed, followed by maintenance chemotherapy, usually with alkylating agents. In Europe, the so-called Packer regimen, together with cisplatin-etoposide regimens, is the most commonly used chemotherapy option. Targeted treatment approaches have not yet been implemented, although tumour biology is well understood and offers personalized approaches, especially for the SHH subgroup. At relapse, rapid resistance occurs frequently, necessitating repositioning of these agents in an earlier treatment phase. Due to the good to intermediate prognosis, patients with medulloblastoma require structured long-term clinical follow-up including MRI of the brain, monitoring of side effects, and psychosocial and fertility counselling. Recently, clinical trials have been initiated with the aim of de-escalating treatment to reduce toxicity and adding targeted therapies to increase efficacy, with the main goal of therapy to cure the tumour while maintaining the physical and psychosocial integrity of affected patients. This article summarizes our opinion on the diagnosis and treatment of medulloblastoma in adults.
Topics: Adult; Cerebellar Neoplasms; Hedgehog Proteins; Humans; Medulloblastoma; Neoplasm Recurrence, Local; Prospective Studies
PubMed: 34118771
DOI: 10.1016/j.esmoop.2021.100173 -
Oncogene Mar 2024Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection,... (Review)
Review
Medulloblastoma is one of the most common malignant pediatric brain tumors derived from posterior fossa. The current treatment includes maximal safe surgical resection, radiotherapy, whole cranio-spinal radiation and adjuvant with chemotherapy. However, it can only limitedly prolong the survival time with severe side effects and relapse. Defining the intratumoral heterogeneity, cellular origin and identifying the interaction network within tumor microenvironment are helpful for understanding the mechanisms of medulloblastoma tumorigenesis and relapse. Due to technological limitations, the mechanisms of cellular heterogeneity and tumor origin have not been fully understood. Recently, the emergence of single-cell technology has provided a powerful tool for achieving the goal of understanding the mechanisms of tumorigenesis. Several studies have demonstrated the intratumoral heterogeneity and tumor origin for each subtype of medulloblastoma utilizing the single-cell RNA-seq, which has not been uncovered before using conventional technologies. In this review, we present an overview of the current progress in understanding of cellular heterogeneity and tumor origin of medulloblastoma and discuss novel findings in the age of single-cell technologies.
Topics: Child; Humans; Medulloblastoma; Cerebellar Neoplasms; Neoplasm Recurrence, Local; Brain Neoplasms; Recurrence; Carcinogenesis; Tumor Microenvironment
PubMed: 38355808
DOI: 10.1038/s41388-024-02967-9 -
Pediatric Hematology and Oncology Sep 2012Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignancy of the central nervous system. Classified as a primitive neural... (Review)
Review
Medulloblastoma (MB) is a cancer of the cerebellum and the most common primary pediatric malignancy of the central nervous system. Classified as a primitive neural ectoderm tumor; it is thought to arise from granule cell precursors in the cerebellum. The standard of care consists of surgery, chemotherapy and age-dependent radiation therapy. Despite aggressive multimodality therapy; approximately 30% of MB patients remain incurable. Moreover, for long-term survivors, the treatment related sequelae are often debilitating. Side effects include cerebellar mutism, sterility, neurocognitive deficits, and a substantial risk of developing secondary cancers. In a quest for more effective and targeted therapies, scientists have begun to investigate the biological events that not only initiate but also sustain the malignant phenotype in MB. Of particular interest is, the role of the tumor microenvironment in tumor pathogenesis. This review seeks to highlight several key processes observed in cancer biology, particularly the involvement of the tumor microenvironment, with relevant examples from MB.
Topics: Animals; Cerebellar Neoplasms; Humans; Medulloblastoma; Tumor Microenvironment
PubMed: 22742590
DOI: 10.3109/08880018.2012.698372 -
Acta Bio-medica : Atenei Parmensis Jun 2020The lack of success of standard therapies for medulloblastoma has highlighted the need to plan a new therapeutic approach. The purpose of this article is to provide an... (Review)
Review
BACKGROUND
The lack of success of standard therapies for medulloblastoma has highlighted the need to plan a new therapeutic approach. The purpose of this article is to provide an overview of the novel treatment strategies based on the molecular characterization and risk categories of the medulloblastoma, also focusing on up-to-date relevant clinical trials and the challenges in translating tailored approaches into clinical practice.
METHODS
An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites about molecular classification of medulloblastomas, ongoing clinical trials and new treatment strategies. Only articles in the English language and published in the last five years were selected. The research was refined based on the best match and relevance.
RESULTS
A total 58 articles and 51 clinical trials were analyzed. Trials were of phase I, II, and I/II in 55%, 33% and 12% of the cases, respectively. Target and adoptive immunotherapies were the treatment strategies for newly diagnosed and recurrent medulloblastoma in 71% and 29% of the cases, respectively.
CONCLUSION
Efforts are focused on the fine-tuning of target therapies and immunotherapies, including agents directed to specific pathways, engineered T-cells and oncoviruses. The blood-brain barrier, chemoresistance, the tumor microenvironment and cancer stem cells are the main translational challenges to be overcome in order to optimize medulloblastoma treatment, reduce the long-term morbidity and increase the overall survival.
Topics: Brain Neoplasms; Cerebellar Neoplasms; Humans; Immunotherapy; Medulloblastoma; Tumor Microenvironment
PubMed: 32608377
DOI: 10.23750/abm.v91i7-S.9958 -
Journal of Molecular Medicine (Berlin,... Oct 2015Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly... (Review)
Review
Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large-scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review, we highlight, in a subgroup-specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Genetic Predisposition to Disease; Hedgehog Proteins; Humans; Medulloblastoma; Wnt Proteins
PubMed: 26350064
DOI: 10.1007/s00109-015-1333-8 -
Cancer Reports (Hoboken, N.J.) May 2022Medulloblastoma is the most common malignant brain tumor of childhood and is considered a tumor with low mutational burden (~1 Mut/Mb). Therefore, though the...
BACKGROUND
Medulloblastoma is the most common malignant brain tumor of childhood and is considered a tumor with low mutational burden (~1 Mut/Mb). Therefore, though the medulloblastoma genomes have been extensively characterized in literature, reports on potential hypermutations and underlying mutagenic processes in medulloblastomas are limited.
AIM
In this report, we studied the landscape of mutational burden in primary and recurrent medulloblastoma. Furthermore, we wanted to understand the differences in underlying mutagenic mechanisms in medulloblastoma with low and high mutational burdens.
METHODS
Fifty-three primary and recurrent medulloblastoma genomic sequence were downloaded from the European Genome Archive as BAM files. Thirty-three cases were obtained from formalin-fixed paraffin-embedded tissues from pathology diagnostic archives of Spectrum Health and Cooperative Human Tissue Network. Somatic mutations were called using Mutect2, following best practices guidelines for Genome Analysis Toolkit V4. Mutational signatures were analyzed using deconstructSigs.
RESULTS
We identified nine medulloblastoma cases with high mutational burden (>5 Mut/Mb). Of them, five cases met the criteria of hypermutation (>10Mut/Mb), two of the five tumors had canonical mutations in the POLE proof-reading domain, where a large proportion of mutations in these tumor genomes contributed to signature 10. The hypermutated cases also demonstrated mutational signatures 14, 15, and 21, indicating the role of mis match repair deficiency in their mutagenesis. Of the four known molecular subgroups in medulloblastoma-SHH, WNT, Group 3, and Group 4-both the POLE-mutated cases belonged to the SHH subgroup. This report identifies rare cases of hypermutation in medulloblastoma driven by defects in DNA repair mechanisms.
CONCLUSION
Hypermutation in medulloblastoma can impact therapeutic decisions, especially at recurrence in otherwise fatal high risk SHH-medulloblastomas. A defect in DNA repair leading to SHH -medulloblastoma is yet another important mechanism that should be further investigated in the genesis of these tumors. Therefore, this report provides important scientific and clinical rationale for future research looking for incidence of hypermutation in large cohorts of medulloblastoma patients.
Topics: Brain Neoplasms; Cerebellar Neoplasms; Genomics; Humans; Medulloblastoma; Mutation
PubMed: 34351088
DOI: 10.1002/cnr2.1521 -
Cancer Letters Nov 2017Medulloblastoma is the most common solid tumor among children. Current therapeutic strategies for this malignancy include surgical resection, radiation therapy and... (Review)
Review
Medulloblastoma is the most common solid tumor among children. Current therapeutic strategies for this malignancy include surgical resection, radiation therapy and chemotherapy. However, these treatments are accompanied with serious side effects such as neurological complications and psychosocial problems, due to the severity of treatment on the developing nervous system. To solve this problem, novel therapeutic approaches are currently being investigated. One of them is targeting human cytomegalovirus in medulloblastoma cancer cells. However, this approach is still under debate, since the presence of cytomegalovirus in medulloblastomas remains controversial. In this review, we discuss the current controversies on the role of cytomegalovirus in medulloblastoma oncogenesis and the potential of cytomegalovirus as a novel (immuno)therapeutic target.
Topics: Animals; Cerebellar Neoplasms; Cytomegalovirus; Humans; Immunotherapy; Medulloblastoma; Oncogenes
PubMed: 28844716
DOI: 10.1016/j.canlet.2017.08.024