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Multi-omics analysis of intertumoral heterogeneity within medulloblastoma uncharted-pathway subtypes

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Abstract

Medulloblastoma is a common pediatric malignant brain tumor. There were four consensus molecular subgroups (WNT, SHH, Group3 and Group4). Group 3 and Group 4 tumors exhibited a great degree of transcriptional overlap, and were neither derived from exact pathway aberration. We investigated transcriptional and chromatin accessibility of medulloblastoma by multi-omics single-cell analysis. Our work identified inter- and intra-tumoral heterogeneity within the Group 3, Group 4 and Group 3/4 intermediate subgroups. Unsupervised cluster of each tumor identified 9 cell clusters with transcriptional profiles and 6 cell clusters with chromatin accessibility profiles. OTX2 had the highest activity and expression level across the clusters in a special cluster based on open chromatin single-cell profilings. We identified multiple genes as a significant targeted gene within the OTX2 target genes, which made sense in prognosis. We analyzed the copy-number-variations which presented with expected subgroup distribution from transcriptional and chromatin accessibility profiles. Collectively, these data provide novel insights into Group 3 and Group 4 medulloblastoma and provide a potential therapeutic target.

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Acknowledgements

This research was funded by the National Natural Science Foundation of China (No. 81870834), Intergovernmental cooperation on international scientific and technological innovation (2017YFE0121200) and Special project of pediatrics of collaborative development center of Beijing hospital administration (No. XTYB201817).

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Authors and Affiliations

  1. Department of Pediatric Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Zhicen Li & Jian Gong

  2. MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Yifan Wei, Yanqiu Shao & Lei Tang

Authors
  1. Zhicen Li
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  2. Yifan Wei
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  3. Yanqiu Shao
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  4. Lei Tang
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  5. Jian Gong
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by ZL, YW, YS, and LT. The first draft of the manuscript was written by ZL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jian Gong.

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The authors declare that they have no conflict of interest. All authors consent for publication.

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This research with approved by the research ethics committee of the Beijing Tiantan Hospital, Capital Medical University, Beijing and had been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study. Details that might disclose the identity of the subjects under study should be omitted.

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Li, Z., Wei, Y., Shao, Y. et al. Multi-omics analysis of intertumoral heterogeneity within medulloblastoma uncharted-pathway subtypes. Brain Tumor Pathol 38, 234–242 (2021). https://doi.org/10.1007/s10014-021-00400-7

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  • DOI: https://doi.org/10.1007/s10014-021-00400-7

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