Dataset Information

A transcriptome-based classifier to determine molecular subtypes in medulloblastoma.

ABSTRACT: Medulloblastoma is a highly heterogeneous pediatric brain tumor with five molecular subtypes, Sonic Hedgehog TP53-mutant, Sonic Hedgehog TP53-wildtype, WNT, Group 3, and Group 4, defined by the World Health Organization. The current mechanism for classification into these molecular subtypes is through the use of immunostaining, methylation, and/or genetics. We surveyed the literature and identified a number of RNA-Seq and microarray datasets in order to develop, train, test, and validate a robust classifier to identify medulloblastoma molecular subtypes through the use of transcriptomic profiling data. We have developed a GPL-3 licensed R package and a Shiny Application to enable users to quickly and robustly classify medulloblastoma samples using transcriptomic data. The classifier utilizes a large composite microarray dataset (15 individual datasets), an individual microarray study, and an RNA-Seq dataset, using gene ratios instead of gene expression measures as features for the model. Discriminating features were identified using the limma R package and samples were classified using an unweighted mean of normalized scores. We utilized two training datasets and applied the classifier in 15 separate datasets. We observed a minimum accuracy of 85.71% in the smallest dataset and a maximum of 100% accuracy in four datasets with an overall median accuracy of 97.8% across the 15 datasets, with the majority of misclassification occurring between the heterogeneous Group 3 and Group 4 subtypes. We anticipate this medulloblastoma transcriptomic subtype classifier will be broadly applicable to the cancer research and clinical communities.

SUBMITTER: Rathi KS

PROVIDER: S-EPMC7654754 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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A transcriptome-based classifier to determine molecular subtypes in medulloblastoma.

Rathi Komal S KS Arif Sherjeel S Koptyra Mateusz M Naqvi Ammar S AS Taylor Deanne M DM Storm Phillip B PB Resnick Adam C AC Rokita Jo Lynne JL Raman Pichai P

PLoS computational biology 20201029 10

Medulloblastoma is a highly heterogeneous pediatric brain tumor with five molecular subtypes, Sonic Hedgehog TP53-mutant, Sonic Hedgehog TP53-wildtype, WNT, Group 3, and Group 4, defined by the World Health Organization. The current mechanism for classification into these molecular subtypes is through the use of immunostaining, methylation, and/or genetics. We surveyed the literature and identified a number of RNA-Seq and microarray datasets in order to develop, train, test, and validate a robus ...[more]

PMID: 33119584

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Project description:Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

Dataset Information

A transcriptome-based classifier to determine molecular subtypes in medulloblastoma.

Publications

A transcriptome-based classifier to determine molecular subtypes in medulloblastoma.

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