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Published on: June 7, 2018
Multi-omics analysis of intertumoral heterogeneity within medulloblastoma uncharted-pathway subtypes
Zhicen Li1, Yifan Wei2, Yanqiu Shao2
1Department of Pediatric Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
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.
Insights
This study reveals significant heterogeneity in Group 3 and Group 4 medulloblastoma using single-cell analysis. OTX2 was identified as a potential therapeutic target for these pediatric brain tumors.
Area of Science:
- Oncology
- Genetics
- Pediatric Medicine
Background:
- Medulloblastoma is a common pediatric malignant brain tumor with four consensus molecular subgroups.
- Group 3 and Group 4 medulloblastomas show transcriptional overlap and lack clear pathway aberrations.
Purpose of the Study:
- To investigate transcriptional and chromatin accessibility in medulloblastoma using multi-omics single-cell analysis.
- To identify heterogeneity within Group 3, Group 4, and intermediate subgroups.
Main Methods:
- Multi-omics single-cell analysis was employed to profile transcriptional and chromatin accessibility.
- Unsupervised clustering identified distinct cell clusters based on transcriptional and chromatin profiles.
Main Results:
- Inter- and intra-tumoral heterogeneity was identified within Group 3, Group 4, and intermediate subgroups.
- OTX2 demonstrated high activity and expression, with identified target genes showing prognostic significance.
- Copy-number-variations aligned with expected subgroup distributions.
Conclusions:
- The study provides novel insights into the heterogeneity of Group 3 and Group 4 medulloblastomas.
- OTX2 emerges as a potential therapeutic target for these pediatric brain tumors.
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