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Resolving medulloblastoma cellular architecture by single-cell genomics.

ABSTRACT: Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.

SUBMITTER: Hovestadt V

PROVIDER: S-EPMC6754173 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Resolving medulloblastoma cellular architecture by single-cell genomics.

Hovestadt Volker V Smith Kyle S KS Bihannic Laure L Filbin Mariella G MG Shaw McKenzie L ML Baumgartner Alicia A DeWitt John C JC Groves Andrew A Mayr Lisa L Weisman Hannah R HR Richman Alyssa R AR Shore Marni E ME Goumnerova Liliana L Rosencrance Celeste C Carter Robert A RA Phoenix Timothy N TN Hadley Jennifer L JL Tong Yiai Y Houston Jim J Ashmun Richard A RA DeCuypere Michael M Sharma Tanvi T Flasch Diane D Silkov Antonina A Ligon Keith L KL Pomeroy Scott L SL Rivera Miguel N MN Rozenblatt-Rosen Orit O Rusert Jessica M JM Wechsler-Reya Robert J RJ Li Xiao-Nan XN Peyrl Andreas A Gojo Johannes J Kirchhofer Dominik D Lötsch Daniela D Czech Thomas T Dorfer Christian C Haberler Christine C Geyeregger Rene R Halfmann Angela A Gawad Charles C Easton John J Pfister Stefan M SM Regev Aviv A Gajjar Amar A Orr Brent A BA Slavc Irene I Robinson Giles W GW Bernstein Bradley E BE Suvà Mario L ML Northcott Paul A PA

Nature 20190724 7767

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup ...[more]

PMID: 31341285

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Project description:Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the dataset. Immunohistochemistry for subgroup-specific ‘signature’ genes was used to determine subgroup affiliation for 294 non-overlapping medulloblastomas on two independent tissue microarrays (TMAs). Multiple unsupervised analyses of transcriptional profiles identified four distinct, non-overlapping molecular variants: WNT, SHH, Group C, and Group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group D) could reliably and uniquely classify formalin fixed medulloblastomas in ~98% of cases. Group C patients (NPR3 +ve tumors) exhibited a significantly diminished progression free and overall survival irrespective of their metastatic status. Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma sub-classification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. A total of 103 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.

Dataset Information

Resolving medulloblastoma cellular architecture by single-cell genomics.

Publications

Resolving medulloblastoma cellular architecture by single-cell genomics.

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