1. Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma
- Author
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Chapman, Owen S, Luebeck, Jens, Sridhar, Sunita, Wong, Ivy Tsz-Lo, Dixit, Deobrat, Wang, Shanqing, Prasad, Gino, Rajkumar, Utkrisht, Pagadala, Meghana S, Larson, Jon D, He, Britney Jiayu, Hung, King L, 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, Levy, Michael L, Hobbs, Charlotte, Scheuermann, Richard H, Crawford, John R, Pomeroy, Scott L, Rich, Jeremy N, Zhang, Xinlian, Chang, Howard Y, Dixon, Jesse R, Bagchi, Anindya, Deshpande, Aniruddha J, Carter, Hannah, Fraenkel, Ernest, Mischel, Paul S, Wechsler-Reya, Robert J, Bafna, Vineet, Mesirov, Jill P, and Chavez, Lukas
- Subjects
Agricultural ,Veterinary and Food Sciences ,Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Agricultural Biotechnology ,Rare Diseases ,Precision Medicine ,Cancer ,Pediatric Cancer ,Pediatric ,Cancer Genomics ,Human Genome ,Brain Cancer ,Brain Disorders ,Humans ,DNA ,Circular ,Medulloblastoma ,Retrospective Studies ,Neoplasms ,Oncogenes ,Cerebellar Neoplasms ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Circular 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.
- Published
- 2023