Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma
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Published:2023-11-09
Issue:12
Volume:55
Page:2189-2199
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Chapman Owen S., Luebeck Jens, Sridhar Sunita, Wong Ivy Tsz-LoORCID, Dixit Deobrat, Wang Shanqing, Prasad Gino, Rajkumar Utkrisht, Pagadala Meghana S.ORCID, Larson Jon D.ORCID, He Britney JiayuORCID, Hung King L.ORCID, Lange Joshua T., Dehkordi Siavash R., Chandran Sahaana, Adam Miriam, Morgan Ling, Wani Sameena, Tiwari Ashutosh, Guccione Caitlin, Lin Yingxi, Dutta Aditi, Lo Yan Yuen, Juarez Edwin, Robinson James T., Korshunov Andrey, Michaels John-Edward A., Cho Yoon-Jae, Malicki Denise M., Coufal Nicole G.ORCID, Levy Michael L., Hobbs Charlotte, Scheuermann Richard H., Crawford John R., Pomeroy Scott L., Rich Jeremy N., Zhang Xinlian, Chang Howard Y.ORCID, Dixon Jesse R.ORCID, Bagchi Anindya, Deshpande Aniruddha J.ORCID, Carter HannahORCID, Fraenkel ErnestORCID, Mischel Paul S.ORCID, Wechsler-Reya Robert J.ORCID, Bafna VineetORCID, Mesirov Jill P.ORCID, Chavez LukasORCID
Abstract
AbstractCircular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke St. Baldrick’s Foundation UC | University of California, San Diego U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine U.S. Department of Health & Human Services | NIH | National Cancer Institute Cancer Research UK National Brain Tumor Society U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences Stanford University Hyundai Motor Group | Hyundai Motor America | Hyundai Hope On Wheels
Publisher
Springer Science and Business Media LLC
Reference110 articles.
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