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OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS

Extrachromosomal circular DNA (ecDNA) is an important driver of particularly aggressive human cancers. However, the prevalence of ecDNA, and its role in tumor development and progression in the different molecular subgroups of medulloblastoma (MB), remain unknown. To answer these questions, we have...

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Autores principales: Chapman, Owen, Luebeck, Jens, Wang, Shanqing, Garancher, Alexandra, Larson, Jon, Lange, Joshua, Wong, Ivy Tsz Lo, Crawford, John, Pomeroy, Scott, Mischel, Paul, Fraenkel, Ernest, Wechsler-Reya, Robert, Bafna, Vineet, Mesirov, Jill, Chavez, Lukas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168199/
http://dx.doi.org/10.1093/neuonc/noab090.148
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author Chapman, Owen
Luebeck, Jens
Wang, Shanqing
Garancher, Alexandra
Larson, Jon
Lange, Joshua
Wong, Ivy Tsz Lo
Crawford, John
Pomeroy, Scott
Mischel, Paul
Fraenkel, Ernest
Wechsler-Reya, Robert
Bafna, Vineet
Mesirov, Jill
Chavez, Lukas
author_facet Chapman, Owen
Luebeck, Jens
Wang, Shanqing
Garancher, Alexandra
Larson, Jon
Lange, Joshua
Wong, Ivy Tsz Lo
Crawford, John
Pomeroy, Scott
Mischel, Paul
Fraenkel, Ernest
Wechsler-Reya, Robert
Bafna, Vineet
Mesirov, Jill
Chavez, Lukas
author_sort Chapman, Owen
collection PubMed
description Extrachromosomal circular DNA (ecDNA) is an important driver of particularly aggressive human cancers. However, the prevalence of ecDNA, and its role in tumor development and progression in the different molecular subgroups of medulloblastoma (MB), remain unknown. To answer these questions, we have assembled a multi-institutional retrospective cohort of 472 MB patients with available whole genome sequencing (WGS) data, drawing from three cancer genomic data repositories and covering all MB subgroups (WNT, SHH, Group 3 and Group 4). Using recent computational methods to detect and reconstruct ecDNA, we find ecDNA in 66 patients (14%) and observe that the presence of ecDNA is associated with significantly poorer outcomes. By subgroup, ecDNA was found in 0/24 WNT (0%), 22/109 SHH (20%), 15/107 Group 3 (14%) and 20/181 Group 4 (11%) patients. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. We further analyzed 24 patient-derived xenograft (PDX) and four cell line models of MB tumors. ecDNA was substantially more frequent in patient-derived models (17 of 29, 59%) than in our patient cohort. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identify regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we are currently conducting in-vitro CRISPRi screens targeting regulatory regions on the ecDNA of a MB cell line to determine whether these enhancers promote proliferation. In summary, our study analyzes the frequency, diversity and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.
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spelling pubmed-81681992021-06-02 OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS Chapman, Owen Luebeck, Jens Wang, Shanqing Garancher, Alexandra Larson, Jon Lange, Joshua Wong, Ivy Tsz Lo Crawford, John Pomeroy, Scott Mischel, Paul Fraenkel, Ernest Wechsler-Reya, Robert Bafna, Vineet Mesirov, Jill Chavez, Lukas Neuro Oncol Omics Extrachromosomal circular DNA (ecDNA) is an important driver of particularly aggressive human cancers. However, the prevalence of ecDNA, and its role in tumor development and progression in the different molecular subgroups of medulloblastoma (MB), remain unknown. To answer these questions, we have assembled a multi-institutional retrospective cohort of 472 MB patients with available whole genome sequencing (WGS) data, drawing from three cancer genomic data repositories and covering all MB subgroups (WNT, SHH, Group 3 and Group 4). Using recent computational methods to detect and reconstruct ecDNA, we find ecDNA in 66 patients (14%) and observe that the presence of ecDNA is associated with significantly poorer outcomes. By subgroup, ecDNA was found in 0/24 WNT (0%), 22/109 SHH (20%), 15/107 Group 3 (14%) and 20/181 Group 4 (11%) patients. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. We further analyzed 24 patient-derived xenograft (PDX) and four cell line models of MB tumors. ecDNA was substantially more frequent in patient-derived models (17 of 29, 59%) than in our patient cohort. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identify regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we are currently conducting in-vitro CRISPRi screens targeting regulatory regions on the ecDNA of a MB cell line to determine whether these enhancers promote proliferation. In summary, our study analyzes the frequency, diversity and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches. Oxford University Press 2021-06-01 /pmc/articles/PMC8168199/ http://dx.doi.org/10.1093/neuonc/noab090.148 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Omics
Chapman, Owen
Luebeck, Jens
Wang, Shanqing
Garancher, Alexandra
Larson, Jon
Lange, Joshua
Wong, Ivy Tsz Lo
Crawford, John
Pomeroy, Scott
Mischel, Paul
Fraenkel, Ernest
Wechsler-Reya, Robert
Bafna, Vineet
Mesirov, Jill
Chavez, Lukas
OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
title OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
title_full OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
title_fullStr OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
title_full_unstemmed OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
title_short OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
title_sort omic-01. the landscape of extrachromosomal circular dna in medulloblastoma subgroups
topic Omics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168199/
http://dx.doi.org/10.1093/neuonc/noab090.148
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