Spatial heterogeneity in medulloblastoma

Morrissy, A. Sorana; Cavalli, Florence M.G.; Remke, Marc; Ramaswamy, Vijay; Shih, David; Holgado, Borja L.; Farooq, Hamza; Donovan, Laura; Garzia, Livia; Agnihotri, Sameer; Kiehna, Erin N.; Mercier, Eloi; Mayoh, Chelsea; Papillon‐Cavanagh, Simon; Nikbakht, Hamid; Gayden, Tenzin; Torchia, Jonathon; Picard, Daniel; Merino, Diana M.; Vladoiu, Maria C.; Luu, Betty; Wu, Xiaochong; Daniels, Craig; Horswell, Stuart; Thompson, Yuan; Hovestadt, Volker; Northcott, Paul A.; Jones, David; Peacock, John; Wang, Xin; Mack, Stephen C.; Reimand, Jüri; Albrecht, Steffen; Fontebasso, Adam M.; Thiessen, Nina; Li, Yisu; Schein, Jacqueline E.; Lee, Darlene; Carlsen, Rebecca; Mayo, Michael; Tse, Kane; Tam, Angela; Dhalla, Noreen; Ally, Adrian; Chuah, Eric; Cheng, Young; Plettner, Patrick; Li, Haiyan I.; Corbett, Richard; Wong, Tina; Long, William D.; Loukides, James; Buczkowicz, Pawel; Hawkins, Cynthia; Tabori, Uri; Rood, Brian R.; Myseros, John S.; Packer, Roger J.; Korshunov, Andrey; Lichter, Peter; Kool, Marcel; Pfister, Stefan M.; Schüller, Ulrich; Dirks, Peter B.; Huang, Annie; Bouffet, Éric; Rutka, James T.; Bader, Gary D.; Swanton, Charles; Ma, Yusanne; Moore, Richard A.; Mungall, Andrew J.; Majewski, Jacek; Jones, Steven J.M.; Das, Sunit; Malkin, David; Jabado, Nada; Marra, Marco A.; Taylor, Michael D.

doi:10.1038/ng.3838

Cited by 119 publications

(110 citation statements)

References 52 publications

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“…Medulloblastomas are known to exhibit well-characterized intertumoral heterogeneity, as well as geographic, spatial (metastases) and temporal (at recurrence) heterogeneity 1,23,25,[36][37][38][39][40] . Posterior fossa (cerebellar) ependymomas also show marked intertumoral heterogeneity [15][16][17][18][19]27 , while the intertumoral heterogeneity amongst cerebellar pilocytic astrocytomas is not well characterized 26 .…”

Section: Single Cell Heterogeneity In Human Cerebellar Tumorsmentioning

confidence: 99%

Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Vladoiu

El-Hamamy

Donovan

et al. 2018

Preprint

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Summary: 150 wordsThe study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development.We used single-cell transcriptomics to study >60,000 cells from the developing murine All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Single Cell Heterogeneity In Human Cerebellar Tumorsmentioning

confidence: 99%

Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Vladoiu

El-Hamamy

Donovan

et al. 2018

Preprint

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“…Despite very different transcriptomic profiles and associated genomic alterations, no differences in survival exist between these subtypes. More recently, it has been shown that multiple subtypes coexist in different regions 20 and different cells 12 within the same tumour. This interpatient and intratumoural heterogeneity poses a daunting challenge for research programs aimed at developing targeted therapeutic approaches 21 and may explain the failures of such approaches in this disease.…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA-seq reveals that glioblastoma recapitulates normal brain development

Ayyadhury

et al. 2018

Preprint

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Cancer stem cells are critical for cancer initiation, development, and resistance to treatments. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA-sequencing on 38 296 glioblastoma cells and 22 637 normal human fetal brain cells. Using an unbiased approach, we mapped the lineage hierarchy of the developing human brain and compared the transcriptome of each cancer cell to this roadmap. We discovered a conserved neural trilineage cancer hierarchy with glial progenitor-like cells at the apex. We also found that this progenitor population contains the majority of cancer's cycling cells and is the origin of heterogeneity. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, unravels the origin of glioblastoma heterogeneity, and helps to identify cancer stem cell-specific targets.

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“…We performed a principal component analysis of the DNA methylation data to elucidate drivers of differences in methylation (258 samples, Figure 3a). Included in the analysis were samples from a second cohort 16,21,22 consisting of 61 multi-sector tumor samples from 11 gliomas, and a control cohort of 64 nonneoplastic brain samples. The first principal component (percentage of variance 75%) separated samples based on IDH-status, as indicated by the IDH-mutant and IDH-wildtype samples from the validation cohort ( Figure 3a).…”

Section: Tumor Purity Is An Important Determinant Of Dna Methylation mentioning

confidence: 99%

DNA methylation classification in diffuse glioma shows little spatial heterogeneity after adjusting for tumor purity

Verburg

Barthel

Anderson

et al. 2020

Preprint

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Intratumoral heterogeneity is a hallmark of diffuse gliomas. We used neuronavigation to acquire 133 imageguided and spatially-separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma, which we characterized using DNA methylation arrays. Samples were obtained from regions with and without imaging abnormalities. Methylation profiles were analyzed to devise a three-dimensional reconstruction of genetic and epigenetic heterogeneity. Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and largely explains apparent epigenetic spatial heterogeneity. Indeed, we observed that DNA methylation subtypes are highly conserved in space after adjusting for tumor purity. Genome-wide heterogeneity analysis showed equal or increased heterogeneity among normal tissue when compared to tumor. These findings were validated in a separate cohort of 61 multi-sector tumor and 64 normal samples. Our findings underscore the infiltrative nature of diffuse gliomas and suggest that heterogeneity in DNA methylation is innate to somatic cells and not a characteristic feature of this tumor type.

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Spatial heterogeneity in medulloblastoma

Cited by 119 publications

References 52 publications

Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Single-cell RNA-seq reveals that glioblastoma recapitulates normal brain development

DNA methylation classification in diffuse glioma shows little spatial heterogeneity after adjusting for tumor purity

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