scholarly journals The evolution of medulloblastoma therapy to personalized medicine

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 490 ◽  
Author(s):  
Soma Sengupta ◽  
Daniel Pomeranz Krummel ◽  
Scott Pomeroy
Keyword(s):  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Cancer Genomics ◽  
Wnt Signaling Pathway ◽  
Therapeutic Approaches ◽  
Sonic Hedgehog Signaling ◽  
New Therapeutic Approaches ◽  
Group 4 ◽  
Group 3

Recent advances in cancer genomics have revolutionized the characterization and classification of medulloblastomas. According to the current WHO guidelines, medulloblastomas are now classified into the following molecularly defined groups: Wnt signaling pathway (WNT)-activated, sonic hedgehog signaling pathway (SHH)-activated and tumor suppressor protein p53 (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH (i.e. group 3 and group 4). Importantly, genomic, epigenomic, and proteomic advances have created a potential paradigm shift in therapeutic options. The challenge now is to (i) translate these observations into new therapeutic approaches and (ii) employ these observations in clinical practice, utilizing the classification following a molecular analysis for diagnosis and application of new subgroup-specific targeted therapeutics.

scholarly journals Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 643 ◽  
Author(s):  
Han Zou ◽  
Brad Poore ◽  
Alberto Broniscer ◽  
Ian F. Pollack ◽  
Baoli Hu
Keyword(s):  
Brain Tumor ◽  
Cancer Genomics ◽  
High Rate ◽  
Molecular Heterogeneity ◽  
Epigenetic Alterations ◽  
Cell Of Origin ◽  
Therapeutic Approaches ◽  
Group 4 ◽  
Group 3

Medulloblastoma, the most common pediatric malignant brain tumor, continues to have a high rate of morbidity and mortality in childhood. Recent advances in cancer genomics, single-cell sequencing, and sophisticated tumor models have revolutionized the characterization and stratification of medulloblastoma. In this review, we discuss heterogeneity associated with four major subgroups of medulloblastoma (WNT, SHH, Group 3, and Group 4) on the molecular and cellular levels, including histological features, genetic and epigenetic alterations, proteomic landscape, cell-of-origin, tumor microenvironment, and therapeutic approaches. The intratumoral molecular heterogeneity and intertumoral cellular diversity clearly underlie the divergent biology and clinical behavior of these lesions and highlight the future role of precision treatment in this devastating brain tumor in children.

scholarly journals Immunohistochemical and nanoString-Based Subgrouping of Clinical Medulloblastoma Samples

2020 ◽  
Vol 79 (4) ◽  
pp. 437-447 ◽  
Author(s):  
Colleen E D’Arcy ◽  
Liana Figueiredo Nobre ◽  
Anthony Arnaldo ◽  
Vijay Ramaswamy ◽  
Michael D Taylor ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Expression Profiling ◽  
Ffpe Tissue ◽  
Filamin A ◽  
Study Materials ◽  
Group 4 ◽  
P53 Antibodies ◽  
Group 3 ◽  
Highly Correlated

Abstract The diagnosis of medulloblastoma incorporates the histologic and molecular subclassification of clinical medulloblastoma samples into wingless (WNT)-activated, sonic hedgehog (SHH)-activated, group 3 and group 4 subgroups. Accurate medulloblastoma subclassification has important prognostic and treatment implications. Immunohistochemistry (IHC)-based and nanoString-based subgrouping methodologies have been independently described as options for medulloblastoma subgrouping, however have not previously been directly compared. We describe our experience with nanoString-based subgrouping in a clinical setting and compare this with our IHC-based results. Study materials included FFPE tissue from 160 medulloblastomas. Clinical data and tumor histology were reviewed. Immunohistochemical-based subgrouping using β-catenin, filamin A and p53 antibodies and nanoString-based gene expression profiling were performed. The sensitivity and specificity of IHC-based subgrouping of WNT and SHH-activated medulloblastomas was 91.5% and 99.54%, respectively. Filamin A immunopositivity highly correlated with SHH/WNT-activated subgroups (sensitivity 100%, specificity 92.7%, p < 0.001). Nuclear β-catenin immunopositivity had a sensitivity of 76.2% and specificity of 99.23% for detection of WNT-activated tumors. Approximately 23.8% of WNT cases would have been missed using an IHC-based subgrouping method alone. nanoString could confidently predict medulloblastoma subgroup in 93% of cases and could distinguish group 3/4 subgroups in 96.3% of cases. nanoString-based subgrouping allows for a more prognostically useful classification of clinical medulloblastoma samples.

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